Induction of an adaptive immune response by vaccination is possible for a broad range of infectious diseases or cancers. Antigen-loaded polymeric nanoparticles have recently been shown to possess significant potential as vaccine delivery systems and adjuvants. Here we demonstrate the use of nanoparticles composed of amphiphilic poly(amino acid) derivatives as vaccine adjuvants. We prepared protein-loaded, biodegradable nanoparticles composed of hydrophobically modified poly(gamma-glutamic acid) (gamma-PGA). gamma-PGA hydrophobic derivatives (gamma-hPGA) formed 200 nm-sized nanoparticles in water. The protein-encapsulated gamma-hPGA nanoparticles were efficiently taken up by immature dendritic cells (iDCs). Interestingly, the nanoparticle uptake by iDCs induced DC maturation. The immunization with human immunodeficiency virus (HIV)-1 gp120-encapsulated nanoparticles strongly induced antigen-specific cellular immunity. These results suggest that antigen-loaded gamma-hPGA nanoparticles provide a novel delivery tool for vaccination against viral infections or tumors. This system has potential application as a universal delivery system for protein-based vaccines capable of inducing cytotoxic T lymphocyte (CTL).