Cell-mediated immune responses in DBA/2 mice bearing melanoma tumors (TB-mice) were measured and compared to similar responses in mice without tumors (C-mice). Splenic lymphocytes from TB-mice had a reduced capacity to respond to both B and T-cell mitogens, but TB-mice responded to infection with vaccinia virus by developing a virus-specific cytotoxic T-cell response equal to that measured with splenic effectors prepared from virus-infected C-mice. NK-cell activity, as measured by the in vitro lysis of YAC-1 targets by splenic effectors, was significantly depressed in TB-mice but, after infection of the animals with vaccinia virus, was restored to levels equal to that measured with splenic effectors prepared from C-mice. Doses of vaccinia virus, strain WR which elicited vaccinia-virus-specific cytotoxic T cells or stimulated NK-cell activity, failed to elicit or stimulate cytotoxic effectors specific for S91-melanoma tumor cells.