Background. Xenogeneic DNA immunization can exploit small differences in expressed protein sequence resulting in immune recognition of self-molecules. We hypothesized that immunizing mice with xenogeneic DNA coding for the human melanosomal membrane glycoprotein gp 100 would overcome immune ignorance or tolerance and result in tumor immunity. We also investigated the immunologic mechanisms of the antitumor immunity. Methods. C57BL/6 mice were immunized with DNA coding for human gp 100, mouse gp 100, or control vector by gene gun. After immunization, mice were challenged with a syngeneic melanoma expressing gp 100, and tumor growth was analyzed. Mice deficient in major histocompatibility complex class I or class II molecules were similarly studied to assess the immunologic mechanism of the tumor protection. Results. There was significant tumor protection after vaccination with xenogeneic human gp 100 DNA. Class I, but not class II, major histocompatibility complex molecules were required for tumor immunity. In addition, mice immunized with human gp 100 demonstrated autoimmunity manifested as coat color depigmentation. Conclusions. Immunization with xenogeneic DNA coding for the melanosomal glycoprotein gp 100 results in tumor protection and autoimmune depigmentation. These results show that xenogeneic DNA vaccines can lead to cancer immunity without CD4+ T-cell help with potential implications for rational vaccine design.