A mouse glioblastoma cell line, termed GL261, was shown to express high levels of proteins involved in melanin biosynthesis such as the tyrosinase-related protein-2 (TRP-2), which is commonly overexpressed in melanoma cells. Mice injected with GL261 cells developed a CD8(+) T-cell response to TRP-2 and a DNA vaccine expressing human (h)TRP-2 induced CD8(+) T cells that recognized TRP-2 expressed by GL261 cells indicating that this melanoma-associated antigen may be suited for active immunotherapy of glioblastoma. Mice vaccinated with a DNA vaccine expressing TRP-2 were partially protected against subcutaneous, intravenous, or intracerebral challenge with the glioblastoma cells. Vaccine-induced protection against intracerebral challenge required both CD4(+) and CD8(+) T cells. Vaccine efficacy was enhanced upon addition of IL-12 as a genetic adjuvant. These results indicate that this well-defined melanoma-associated antigen can induce an adaptive immune response, which limits the intracerebral progression of a glioblastoma.