We recently demonstrated differential susceptibility of cells expressing viral antigen to killing by antigen-specific cytotoxic T lymphocytes (CTLs). In addition, interferon-gamma (IFN-gamma) has been implicated in the clearance of some viruses from tissues. We explored the role of IFN-gamma in the cytotoxicity of Sendai virus-specific CTLs against virus- infected RL male 1 (T cell leukemia) or Meth A (fibrosarcoma) cells, as well as the growth of subcutaneously (s.c.) transplanted, virus-infected cells in IFN-gamma(+/+) or IFN-gamma(-/-) mice of the syngeneic strain (BALB/c). Sendai virus-specific CTLs were cytotoxic against virus- infected RL male 1 cells, and s.c. transplanted, virus-infected RL male 1 cells were acutely rejected from IFN-gamma(+/+) or IFN-gamma(-/-) mice. In contrast, the CTLs were inactive toward virus-infected Meth A cells, but s.c. transplanted, virus-infected Meth A cells were acutely rejected from IFN-gamma(+/+) but not IFN-gamma(-/-) mice. The s.c. growth of virus-infected Meth A cells in the mutant mice was markedly inhibited by s.c. injections of IFN-gamma, and the rejection from IFN-gamma(+/+) mice was delayed after specific elimination of macrophages by intravenous (i.v.) injections of dichloromethylene diphosphonate-containing liposomes. These results suggest an essential role of IFN-gamma and involvement of macrophage in the rejection of CTL-resistant, virus-infected cells.