Vaccine development efforts against HIV-1 have been hindered because of the high mutation rate of the virus, and limitations for direct testing of HIV antigens in animal models to discern the nature of protective immunity. We developed a multivalent vaccine comprised of highly conserved HIV envelope peptide cocktail focused on priming antigen-specific helper T cell and CTL responses. Here we report protection of rhesus macaques against pathogenic SHIV(89.6P) challenge through priming cell-mediated immunity by prophylactic vaccination with the peptide-cocktail delivered by dendritic cells. Compared to monkeys mock-vaccinated or immunized with the peptide cocktail using IFA, vaccination with peptide cocktail-pulsed DC showed significant protection from AIDS-associated mortality and reduction in plasma viremia to undetectable levels.