The T cell responses of Moloney leukemia virus (MoLV)-infected preleukemic BALB/c mice were examined. The major in vitro response detectable was T cell blastogenesis in response to the major viral envelope protein MoLV gp71 and an internal viral protein p12. The majority of the preleukemic mice had readily detectable responses to gp71, whereas the presence of a response to p12 was less consistent. With both antigens, T cell blastogenesis showed typical antigen response characteristics similar to those detected in other immune responses to C-type viruses. Proliferation was dependent on a Thy-1+, Lyt-1+, 2- population and was macrophage-independent. In contrast to most immune responses to C-type viruses, which are temporally restricted, T cell blastogenesis was detectable throughout the preleukemic period of 4 to 16 wk of age. During this period neither gp71-specific T cells nor PHA-responsive T cells were found to express viral antigens. The correlations between T cells responding to gp71 and leukemia were examined. Under conditions in which MoLV inoculation of BALB/c mice does not induce leukemia, no T cell responses were deectable. These results suggest a causal relationship between the presence of antigen-specific T cells and the ability of MoLV to induce leukemia. The results are discussed with reference to the possible role of chronic immune stimulation in virus-induced leukemogenesis.