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Background: The use of biological agents in the treatment of various inflammatory and malignancy conditions has expanded rapidly. However, these agents can induce hypersensitivity reactions, posing significant clinical challenges. Methods: We conducted a retrospective study that included nine patients with severe asthma who experienced hypersensitivity reactions to biological agents (omalizumab, benralizumab and dupilumab). Results: Hypersensitivity reactions to biologicals in severe asthma were observed in 9 of 68 patients treated. In five cases, treatment was stopped or changed to another available biological, and for four patients administered under close surveillance, titrated provocation or desensitization was applied. Successful desensitization was achieved in three of the patients, allowing them to continue therapy without adverse reactions. Improvements in asthma control were observed post-desensitization, leading to the reduced need for systemic steroid treatments and an increase in quality of life. Conclusions: This study highlights the importance of recognizing hypersensitivity reactions to biologicals to have an appropriate approach for patients with severe asthma. As an effective approach for patients experiencing hypersensitivity reactions to biological agents, desensitization allows treatment continuation.