Friend murine retrovirus complex induces acute and fatal erythroleukemia when inoculated into immunocompetent adult mice. The development of leukemia after inoculation of Friend virus complex is controlled by several host genes. Some of the host genes influence immune responses against the viral antigens. Both CD4-positive T helper cells and CD8-positive cytotoxic T-lymphocytes specific for Friend viral antigens are required for spontaneous resistance against the virally induced leukemia. We have identified two separate T helper cell epitopes in the gp70 envelope glycoprotein encoded by the helper component of Friend virus complex. Immunization of mice with a synthetic peptide that represented one of the two T helper cell epitopes by a single injection with an adjuvant induced potent protective immunity against Friend virus-induced leukemia, even in the absence of CD8-positive T lymphocytes. In the immunized mice, virus-infected erythroid progenitor cells were rapidly eliminated from the spleen within two weeks after inoculation of the Friend virus. These data indicate unexpected importance and efficacy of CD4-positive T helper cells in immunity against retrovirus infections.