Abstract HRS/J, hr/hr and hr/+ mice were evaluated for their ability to resist challenge with a syngeneic tumor, HTU, and for their ability to mount a protective immune response when immunized in vivo with inactivated HTU cells previous to challenge with viable tumors. The heterozygous (hr/+) mice responded more strongly than the homozygous (hr/hr) mice. This response was characterized by the presence of an enhanced ability of spleen cells from immunized mice to form blasts in vitro when incubated with purified murine leukemia viruses (MuLV). We conclude that the in vivo response of HRS/J mice against this tumor is directed, in part, against MuLV antigens expressed on the tumor cells and that the relatively weak response of hr/hr spleen cells to these antigens may be mechanistically linked to their tumor susceptibility.