Venom immunotherapy (VIT) with aqueous extracts is considered a life-saving treatment in insect allergy, but systemic side effects are quite common, especially in patients sensitized to Apis mellifera venom. Only a few studies are available regarding depot VIT administered according to the standard weekly schedule, while no data are available for cluster VIT with depot preparations. This study was designed to compare the tolerance of aqueous cluster or rush VIT versus cluster depot VIT in patients sensitized to Apis mellifera. Fifty-five patients with a history of systemic reaction (grade II to IV according to Müller) after an Apis mellifera sting were divided at random into 3 groups. Forty patients were treated with aqueous VIT (20 according to a cluster schedule and 20 according to a rush schedule) and 15 with Depot VIT according to a cluster schedule. All local and systemic side effects were recorded. Four patients belonging to the aqueous-cluster, 4 belonging to the aqueous-rush, and 1 belonging to the depot-cluster schedule had large local reactions after VIT (p < 0.009). Systemic side effects were recorded in 1, 7 and 0 patients (p < 0.003) respectively. No statistically significant difference was found between the two cluster regimens in the frequency of side effects. Depot VIT administered according to a cluster schedule was well tolerated, and its tolerance is better than aqueous-rush VIT for Apis mellifera.