We describe the use of methoxypolyethylene glycol-poly(lactide-co-glycolide) nanoparticles as a delivery system for recombinant hepatitis B surface antigen (HBsAg). Evaluation of the stability and release kinetics of nanoencapsulated HBsAg in vitro in serum revealed an initial burst effect and a subsequent slower release of the antigen. Importantly the antigenicity was not destroyed by the encapsulation process, because upon release it was able to react with an anti-HBs antibody. Bone marrow-derived dendritic cells showed efficient uptake of the nanoparticle vaccine as visualized by confocal imaging. To determine whether nano-encapsulated HBsAg was capable of eliciting an immune response in the absence of an adjuvant, mice were immunized with the nanoparticle vaccine or with nonencapsulated recombinant HBsAg. In mice immunized with the nanoparticle vaccine, anti-HBs antibodies were detected at significantly earlier time points than in mice immunized with the nonencapsulated recombinant HBsAg.