This prospective study over 3 years investigated the safety, immunogenicity, and effectiveness of immunotherapy (IT) with aluminum hydroxide adsorbed insect venom extracts (Alutard SQ, ALK Laboratories) in patients with previous, severe, systemic, IgE-mediated, anaphylactic reactions to Hymenoptera stings. Seventeen patients were treated with honeybee venom (BV), 13 with yellow-jacket venom (YJV), and 5 with both. No severe reactions to IT were noted. Only 3 BV-allergic patients experienced mild systemic reactions of grades I or II (1 per 139 injections) during the increase phase. As for the immunologic data, there was a significant decrease in specific IgE antibodies after 1 year, and a significant increase in specific IgG and IgG4 antibodies on reaching the maintenance dose, with a further rise after 1, 2, and 3 years. Moreover, a significant decrease in anti-IgE autoantibodies was observed in the BV group. Out of the 11 patients that were occasionally restung by the relevant insect (totaling 19 stings in all), only one patient developed mild systemic allergic symptoms after a third sting. In view of these results, we consider IT with aluminum hydroxide adsorbed insect venom extracts to be safe, immunogenic, and effective. The low rate of side-effects may be due to the slow release of the venom in the aluminum hydroxide adsorbed form.