Biodegradable microspheres were prepared to function as a depot system for the controlled release of a model protein antigen bovine serum albumin (BSA). As an approach to achieve its controlled release, microspheres were fabricated blending a high-molecular-weight poly-d,l-lactide-co-glycolide (M(w) = 61,000) with a low-molecular-weight poly-d,l-lactic acid (M(w) = 2000, PLA2000). The effects of PLA2000 on microsphere degradability and release characteristics of BSA from microspheres were investigated. On the basis of the pH change in microsphere suspensions and water uptake of microspheres, the kinetics of microsphere degradation was derived to describe the rate of formation of hydrogen ions due to hydrolysis of ester linkages of polymers. It substantiated that PLA2000-containing microspheres were subject to controlled degradation that was necessary to achieve continuous release profiles of the antigen. Immunization of rabbits by subcutaneous injection of BSA-containing microspheres enhanced the antigenicity of BSA, and significantly increased the duration of humoral immune responses.