Poly(D,L-lactide-co-glycolide) (PLGA) polymers have been used for the production of biodegradable medical sutures and for controlled drug release for decades. Useful characteristics such as in vivo biodegradability, an adjustable release profile, and the very high encapsulation capacity have stimulated immunologists to explore PLGA microspheres (MS) as antigen delivery systems for vaccination for more than 15 yr. In previous studies aiming at the development of“single-dose” vaccines, direct immunization with PLGA MS containing various antigens induced strong and sustained immune responses. We have observed that human immature monocyte-derived dendritic cells (MoDC) prepared for clinical application are able to internalize high numbers of MS without negative effects on their pivotal properties. Furthermore, PLGA-MS-incorporated antigens are effectively processed for presentation on major histo-compatibility complex (MHC) class I and MHC class II molecules by dendritic cells (DCs) in vitro and induced strong cytotoxic T-lymphocyte (CTL) responses in vivo. Taken together, PLGA MS is a promising delivery vehicle for the improvement of current DC-based tumor vaccine protocols.