Background:Venom-induced anaphylaxis (VIA) is a common, potentially life-threatening hypersensitivity reaction associated with (1) a specific symptom profile, (2) specific cofactors, and (3) specific management. Identifying the differences in phenotypes of anaphylaxis is crucial for future management guidelines and development of a personalized medicine approach. Objective:This study aimed to evaluate the phenotype and risk factors of VIA. Methods:Using data from the European Anaphylaxis Registry (12,874 cases), we identified 3,612 patients with VIA and analyzed their cases in comparison with sex- and age-matched anaphylaxis cases triggered by other elicitors (non-VIA cases [n = 3, 605]). Results:VIA more frequently involved more than 3 organ systems and was associated with cardiovascular symptoms. The absence of skin symptoms during anaphylaxis was correlated with baseline serum tryptase level and was associated with an increased risk of a severe reaction. Intramuscular or intravenous epinephrine was administered significantly less often in VIA, in particular, in patients without a history of anaphylaxis. A baseline serum tryptase level within the upper normal range (8–11.5 ng/mL) was more frequently associated with severe anaphylaxis. Conclusion:Using a large cohort of VIA cases, we have validated that patients with intermediate baseline serum tryptase levels (8–11 ng/mL) and without skin involvement have a higher risk of severe VIA. Patients receiving β-blockers or angiotensin-converting enzyme inhibitors had a higher risk of developing severe cardiovascular symptoms (including cardiac arrest) in VIA and non-VIA cases. Patients experiencing VIA received epinephrine less frequently than did cases with non-VIA.