Bromodeoxyuridine-grown B16 melanoma cells (C3471) immunize mice against not only the parent melanoma but also two other C57BL/6 tumors: a mammary adenocarcinoma and a methylcholanthrene-induced sarcoma. We have shown that the endogenous retrovirus induced in C3471 cells by bromodeoxyuridine can persistently infect feral mouse (SC1) cells and that they then become as efficient as C3471 cells in preventing tumors. Uninfected SC1 cells cannot protect. Neither C3471 nor virus-infected SC1 can prevent B6MS5 or B6MS7, two other non-virus-producing sarcomas, from forming tumors. Meth 4, mammary adenocarcinoma, and L-cells produce retrovirus and prevent melanoma formation in half the mice challenged. Significantly, C57BL/6 mice homozygous for the beige mutation are unable to reject melanoma challenge after C3471 immunization, although their normal littermates do so efficiently. We conclude that production of retrovirus is in some way responsible for the cross-reactive immunizing capacity of C3471 cells and that cells in which the beige mouse is deficient play a role in the rejection process. Beige mice have been shown to be deficient in natural killer cells and abnormal in macrophage kinetics. In addition, C3471-induced protection against B559 melanoma appears to involve host cells sensitive to anti-thymocyte and anti-lymphocyte sera. We hypothesize that the retrovirus-producing cells may cause induction of interferon, which augments the cytocidal activity of natural killer cells and macrophages, killing sensitive tumor cells.