Summary: Prior inoculation of the simian papovavirus SV40 was shown to protect hamsters against challenge with cells transformed by SV40 either in vitro or in vivo. When approximately 102 to 104 cells were used as challenge inoculum, tumor growth was either prevented or delayed in the resistant hamsters. When tumors developed in immune animals, the neoplasms were retarded and their size was generally smaller than in the control animals. Similar results were obtained by intracerebral, subcutaneous or cheek pouch inoculation of tumorigenic cells. With cell inocula approaching or exceeding 105 cells, however, protection was no longer evident. The resistance demonstrated was not due to antiviral antibody. Heat-inactivated virus did not confer protection. Resistance, though of lesser degree, was witnessed in hamsters inoculated with ruptured cells that had been transformed by SV40 virus. The observations suggest the presence in transformed cells of immunologically related cellular antigens. The inoculation of SV40 transformed cells into hamsters previously inoculated with one of the papovaviruses indicated a high degree of protection conferred by the homologous SV40 virus and none by polyoma virus. The human wart virus and the Shope papilloma virus seemed to produce a limited degree of protection.