A significant emphasis has been placed on the development of adjuvants and/or delivery systems to improve both antibody production and cell-mediated immune responses. We previously reported on a novel anionic nanoparticle, which led to enhanced humoral and T helper type-1 (Th1) biased immune responses in mice when coated with cationized model antigen. Tat (1–72) is a conserved regulatory HIV-1 protein. It was hypothesized that HIV vaccine strategies employing Tat (1–72) may be a promising approach. Although previous reports have suggested that Tat (1–86) may be immunosuppressive, it was demonstrated in this present study that Tat (1–72) was not immunosuppressive when co-administered to mice with ovalbumin (OVA). Tat (1–72) was coated on novel anionic nanoparticles. BALB/c mice were immunized with Tat (5μg)-coated nanoparticles (15μg) by subcutaneous injection on days 0 and 14. Antibody and cytokine release were determined on day 28 and compared to Tat (5μg) adjuvanted with Alum (15μg) as a Th2 control, Tat (5μg) adjuvanted with Lipid A (50μg) as a Th1 control. Immunization of BALB/c mice with Tat-coated nanoparticles resulted in antibody levels (IgG and IgM) comparable to those elicited from Tat and Alum. However, Tat-coated nanoparticles led to a Th1 biased immune response. The IFN-γ release from splenocytes with Tat-coated nanoparticles was comparable to that from mice immunized with Tat and Lipid A, and 3.3-fold greater than that from mice immunized with Tat and Alum. These studies warrant further investigation of these nanoparticles to enhance both antibody and cellular-based immune responses.