The influence of murine α-fetoprotein (AFP) on the threshold dose, mean tumor size, regression time, and number of progressors for Moloney sarcoma virus-(MSV) induced tumors in BALB/c mice was studied. AFP-treated mice developed larger tumors, required a longer period for regression, and had a significantly higher mortality. Furthermore, AFP, but not murine albumin or transferrin, allowed growth of tumors when normally subthreshold doses of virus were injected. These effects of AFP could be removed by pretreatment and precipitation of AFP by anti-AFP; on the other hand, they were not altered by dialysis and were noted at sera levels of approximately 170 to 440 µg/ml. The mechanism of this heightened susceptibility in AFP treated mice to MSV appears to be the generation of a cortisone, radiation sensitive splenic, and not lymph node, suppressor T cell. Indeed, the suppression produced by AFP was antigen nonspecific and could be demonstrated in unmanipulated mice after transfer of spleen cells from AFP-treated donors. This transfer of suppression was noted in IgG and IgA secondary responses to sheep red blood cells as well as by quantitating the response of T cell mitogens on spleen cells. These data suggest that AFP, in pharmacologic doses, either alters a subpopulation of spleen cells to exhibit suppressive function or else that AFP is involved in differential homing patterns of lymphoid cells. The relationships of AFP and immune competence appear broad and suggest the need for comparative studies with other oncofetal antigens.