An examination of cell-mediated immunity (CMI) in susceptible mice infected with Friend leukemia virus (FLV) revealed a marked depression of the delayed hypersensitivity response and its in vitro correlate, macrophage migration inhibition. Spleen lymphocytes from mice sensitized with complete Freund's adjuvant (CFA) and infected with low doses of FLV rapidly lost their ability to produce a migration inhibitory factor (MIF) in response to PPD. With both direct and indirect assays for MIF it was shown that there was a significant decrease in the production of MIF in response to mycobacterial antigens by 3 days post-infection. The degree of suppression correlated with both the infecting dose of FLV and the time post-infection. Mice were protected from FLV induced immunosuppression of CMI by vaccination with FLV. In vitro spleen lymphocyte stimulation with the thymus derived (T) cell specific mitogen, ConA, and with antigen (PPD) was also rapidly suppressed after FLV infection. Macrophages from leukemic mice were able to respond to MIF-rich culture supernatants, but nonadherent spleen lymphocytes from the same mice were not able to generate MIF. Antagonists or inhibitors of MIF were not detected in the supernatants of leukemic spleen lymphocyte cultures. The development of delayed hypersensitivity to tubercle bacilli could be abrogated by infecting with FLV up to 14 days after injection of CFA. These observations indicate that FLV not only inhibits the bone marrow-derived cell function of antibody formation, but also the cell-mediated immune functions which are mediated by T cells and which have been implicated as the surveillance mechanism responsible for controlling the emergence of neoplasia.