Key points
- In rare cases, the body forms antibodies against botulinum toxin, and the treatment can become less effective or stop working [1].
- Factors that have been linked to this include repeat treatments at short intervals, extra injections within 3 weeks of the first treatment, high doses, and complexing proteins in the product [2].
- There are fewer data on how common resistance is in cosmetic treatment than in medical (therapeutic) use [2].
- Even if a test finds antibodies, it does not necessarily predict whether the treatment will actually succeed or fail [3].
- If you feel the effect has decreased, it is a good idea to bring your treatment records and look into the cause together with a specialist.
What does resistance mean?
Botulinum toxin is an injectable medicine that temporarily blocks the signals traveling from nerves to muscles, reducing muscle movement. Of its seven serotypes (types), types A and B are used in treatment [4].
What is commonly called resistance is referred to in the medical literature as secondary nonresponse. It describes cases in which the treatment works at first but later becomes less effective, and most of the reported cases have come from cosmetic treatment [2].
As with other biologic drugs, repeated injections over a long period can lead the body to form antibodies, so that it no longer responds clinically [4]. Neutralizing antibodies, which block the action of the toxin, are a particular concern [2].
How common is it?
Botulinum toxin is regarded as a safe and effective treatment, and cases in which antibodies form and the effect decreases or disappears are described as rare [1]. One review also noted that, compared with other approved biologic drugs, type A products tend to produce low levels of clinically detectable antibodies [3].
However, there are fewer data on how common secondary nonresponse is in cosmetic treatment than in medical use [2]. A 2025 systematic review and meta-analysis pooled 29 studies of patients with cervical dystonia (involuntary tightening of the neck muscles), spasticity (muscle stiffness), and blepharospasm (eyelid spasms), and concluded that the risk of secondary treatment failure and neutralizing antibodies appears to differ by indication and by product [5]. Because these studies looked at the treatment of neurological conditions, the doses and number of treatments may differ from those used in cosmetic treatment.
Factors linked to resistance
A 2025 review of the cosmetic literature named the following treatment-related factors: injections at short intervals of less than 3 months, a high cumulative dose, a high dose at one time, and a booster injection given within 3 weeks of the first treatment [2]. Another review also linked short intervals between doses, booster injections, high doses at one time, and a large amount of antigenic protein to antibody formation [1].
Product-related factors that have been discussed include the manufacturing process, storage conditions, the amount of protein that can act as an antigen, and the presence of complexing proteins attached around the neurotoxin [1, 3]. Improper handling of the toxin or improper injection, infection, and individual characteristics were also named as related factors [2]. It has also been suggested that previous vaccination or past exposure to the toxin may play a role [3].
Are there differences between products?
Botulinum toxin products are not identical to one another, and understanding the characteristics of each product is described as important for choosing a product, preventing dosing errors, and ensuring effectiveness and safety [6]. Among biologic drugs, there are examples of reducing immune reactions by making the protein structure smaller and cutting out unnecessary ingredients, and botulinum toxin products have developed in a similar direction [4].
It has been reported that products that contain only the purified core neurotoxin, without complexing proteins, may have lower overall immunogenicity (the tendency to trigger an immune response) [1]. The 2025 meta-analysis mentioned above compared three type A products, and in patients with cervical dystonia and spasticity, two of the products had significantly higher rates of secondary treatment failure than the third, as well as higher rates of neutralizing antibodies depending on the antibody testing method [5]. According to a review in the cosmetic field, the first two products contain complexing proteins and the third does not [2]. In patients who had received only that third product, no treatment failure caused by an immune response and no persistent neutralizing antibodies were found [5].
However, these results come mainly from the treatment of neurological conditions. The 2025 review in the cosmetic field is a narrative review that also includes expert opinions and recommendations [2]. Which product to use is a matter to discuss with a specialist, taking into account effectiveness, safety, and the purpose of treatment.
If you feel the effect has decreased
If the effect is not what it used to be, that does not always mean antibodies are the cause. Improper handling of the toxin or an unsuitable injection technique are also named as factors in secondary nonresponse [2]. It is also important to check whether the treatment area, the dose, or the condition of the muscles has changed.
Antibody tests include structural tests such as the enzyme-linked immunosorbent assay (ELISA) and biological tests using mice, but there is no consistent relationship between antibodies and the actual clinical response [1]. Even if a test finds antibodies, it does not necessarily predict whether the treatment will succeed or fail [3].
When antibodies have caused the response to stop, it is not easy to manage. A review summarized the main options as using a product with lower immunogenicity, waiting for the neutralizing antibodies to disappear on their own, and switching to a toxin of an immunologically different serotype [1]. It has also been pointed out that because robust data on effective treatment are lacking, prevention is important [2].
What to check during your consultation
Botulinum toxin injections are described as a generally safe procedure when performed by an experienced practitioner, with side effects that are temporary and mostly mild and tolerable [6]. Even so, the response and how long the effect lasts vary from person to person, so keeping a record of the following and sharing it during your consultation can help in looking into the cause.
- When, where, and at what dose you have received injections so far
- The type of product used
- How long the effect lasted after your last treatment
- Any history of extra injections at short intervals
- Any history of botulinum toxin treatment for another medical condition
Frequently asked questions
- Will I develop resistance if I get injections often?
- Repeat treatments at intervals shorter than 3 months, extra injections within 3 weeks of the first treatment, and a high cumulative dose are cited as factors linked to secondary nonresponse [2]. However, cases in which antibodies cause the effect to decrease or disappear are described as rare [1]. It is a good idea to decide on the interval between treatments and the dose with a specialist.
- If the effect seems shorter, does that mean I have developed resistance?
- Not necessarily. Other factors, such as how the toxin is handled and how it is injected, are also linked to secondary nonresponse [2]. It is also known that antibody test results do not necessarily predict the actual effect, so it is a good idea to look into the cause through an examination [3].
- If I develop resistance, will it never work for me again?
- Options that have been described include waiting for the neutralizing antibodies to disappear on their own, or switching to a product with lower immunogenicity or to a different serotype [1]. However, robust data on effective treatment are lacking, so results may vary from person to person [2].
References
- Bellows S, Jankovic J. Immunogenicity Associated with Botulinum Toxin Treatment. Toxins (Basel). 2019.PubMed 31454941DOI
- Kroumpouzos G, Silikovich F. Exploring Nonresponse to Botulinum Toxin in Aesthetics: Narrative Review of Key Trigger Factors and Effective Management Strategies. JMIR Dermatol. 2025.PubMed 40273416DOI
- Naumann M, Boo LM, Ackerman AH, et al. Immunogenicity of botulinum toxins. J Neural Transm (Vienna). 2013.PubMed 23008029DOI
- Carr WW, Jain N, Sublett JW. Immunogenicity of Botulinum Toxin Formulations: Potential Therapeutic Implications. Adv Ther. 2021.PubMed 34515975DOI
- Walter U, Albrecht P, Carr W, et al. Systematic Review and Meta-Analysis of Secondary Treatment Failure and Immunogenicity With Botulinum Neurotoxin A in Multiple Indications. Eur J Neurol. 2025.PubMed 40729416DOI
- Dashtipour K, Pedouim F. Botulinum Toxin: Preparations for Clinical Use, Immunogenicity, Side Effects, and Safety Profile. Semin Neurol. 2016.PubMed 26866493DOI
This article is an English translation of general health information that DOY JUN Plastic Surgery compiled in Korean from the summaries (abstracts) of papers in international academic journals. Treatment methods and results vary depending on each person's condition, so please consult a specialist for an accurate diagnosis and treatment plan.