The role of poly(D,L-lactic-co-glycolic acid, PLGA) microparticles on enhancing immune responses of multiepitope DNA vaccines was investigated in vitro and in vivo. pcDNA-SG encoding T and B cell epitopes of foot-and-mouth disease virus (FMDV) was encapsulated into PLGA microparticles. PLGA microparticles could protect themselves from nuclease degradation in vitro. PLGA-pcDNA-SG microparticles could be uptaken by cells and expressed His-tagged SG immunogen in vitro and in vivo. A prolonged expression and presentation of SG immunogen were observed by confocal laser scanning microscopy in the lymphocytes from the mice incubated with PLGA-pcDNA-SG microparticles, compared with the mice immunized with naked pcDNA-SG. PLGA-pcDNA-SG microparticles displayed a significant stronger immunogenicity than naked DNA vaccines with a higher titer of virus-specific antibody, elevated IFN-gamma production and enhanced lymphocyte proliferation. PLGA-DNA microparticle could elicit augmented humoral and cellular responses with reduced amounts and times of immunization.