Delivery of vaccine formulations into the dermis using antigen-coated microneedle patches is a promising and safe approach due to efficient antigen delivery and safety. We have evaluated an intradermal vaccine using HIV-1 p24 Gag peptide-conjugated polypropylene sulfide nanoparticles (PPS-NP) to induce immunity against HIV-1. This PPS-NP formulation did not accelerate the maturation of blood- or skin-derived subsets of dendritic cells (DCs), either generated in vitro or purified ex vivo, despite efficient uptake in the absence of adjuvant. Moreover, DC-mediated capture of particulate antigen in this form induced potent HIV-1-specific CD4(+) T cell responses, as well as B cell-mediated antibody production. Nanoparticle-based intradermal antigen delivery may therefore provide a new option in the global effort to develop an effective vaccine against HIV-1.