Background: Despite considerable knowledge of allergy and its physiopathology, the only treatment with long-lasting effects for bee venom (BV) allergic patients is venom immunotherapy (VIT). Its efficiency has been recognized worldwide for many years. However, some limitations still result in patient rejection and prevent its use, such as the long treatment period with a total of 30-80 injections administered over three to five years, the high cost of treatment, and the risk of anaphylaxis as a side effect. Objective: In order to overcome these inconveniences, a new formulation for VIT is proposed, consisting of BV encapsulated within microspheres composed of poly-lactide-co-glycolide (MS-PLGA) as a controlled delivery system. Methods: BV-MS-PLGA was prepared by a double emulsion/solvent evaporation method and its biological efficiency was tested by ex vivo macrophage uptake stimuli and in vivo antibody production in mice. Results: BV-MS-PLGA formulations prevented inflammatory reactions by impeding direct contact between BV and the organism/tissue. The increased phagocytosis rate of BV-MS-PLGAs by macrophages allowed for the delivery of antigens directly to the intracellular environment. Furthermore, with the use of BV-MS-PLGAs, antibody production was comparable to traditional VIT (free BV delivered in PBS) with the advantages of protecting the organism against the deleterious effects of BV toxins and reducing the number of injections needed to produce the same protective effect. Conclusion: MS-PLGA is a promising controlled delivery system to deliver BV for VIT.