Background: Anaphylactic reactions are a well-known feature of mastocytosis, particularly in relation to hymenoptera venom stings. Although data on the frequency of drug hypersensitivity reactions is limited in mastocytosis, it is hypothesized that these patients may be predisposed to hypersensitivity reactions to certain drugs, including antibiotics. Nevertheless, this issue has not been systematically investigated. Thus, we investigate the prevalence and clinical features of hypersensitivity reactions to antibiotics (HRA) in mastocytosis. Methods: A 15-year retrospective study was conducted among 239 (≥18 years old) consecutive mastocytosis patients who were investigated in our center. All patients underwent a thorough allergy work-up, where self-reported reactions were individually evaluated by an allergist. Results: Overall, 34 patients (14.2%) were deemed to have HRA. Most patients reacted with cutaneous symptoms (74%), and anaphylaxis was rare, confirmed only in two of 34 patients (0.8%). Beta-lactams were the most common elicitors (63%). There were no differences in age, gender, atopic status and tryptase levels between mastocytosis patients with and without antibiotic hypersensitivity. Conclusions: The present study indicates a similar prevalence of HRA in mastocytosis compared to those of the general population. Moreover, antibiotics appear to be rare elicitors of anaphylaxis in these patients. Hence, our results suggest that mastocytosis patients without a history of HRA may be treated with these drugs without special precautions.