<b><i>Background:</i></b> Severe systemic reactions (SRs) to insect venom are rare in childhood and there are few data on this study population. The aim of our study is to analyze the clinical features and to document the risk factors for severe SRs in children with insect venom allergy. <b><i>Methods:</i></b> Children with SRs after Hymenoptera sting were analyzed. The diagnosis was based on medical history, skin tests and/or specific IgE testing. <b><i>Results:</i></b> Seventy-six children were included [57 boys (75%), mean age 9.8 ± 3.4 years]. The mean age of children at the time of SR was 8.3 ± 3.4 years. Reactions were accounted for <i>Vespula </i>(wasp) venom in 58 (76%) and <i>Apis mellifera</i> (bee) venom in 18 (24%) patients. Twenty-six percent of patients had aeroallergen sensitization and 33% had atopic disease, whereas 66% had experienced previous stings. The upper limb was the most frequent area of sting (43%), and the cutaneous system (99%) was the most frequent involved system. SRs occurred in 59% of patients. Multivariate logistic regression analysis revealed eosinophilia (>5%) [odds ratio (OR) 12.6; confidence interval (CI) 1.5–109.7; p = 0.022], female sex (OR 6.4; CI 1.5–26.9; p = 0.011) and accompanying atopic disease (OR 3.4; CI 1.2–12.3; p = 0.016) as significant risk factors for severe SRs. Ninety-seven percent of patients were admitted to the emergency department; however, epinephrine was used in only 46% of patients. <b><i>Conclusions:</i></b> There was a high frequency of hypersensitivity to wasp venom among the study population, and severe reactions were related to mild eosinophilia, female sex and concomitant atopic diseases. A better understanding of the risk factors may lead to effective utilization of health care sources in the future.