Natural killer (NK) cells control antiviral adaptive immune responses in mice during some virus infections, but the universality of this phenomenon remains unknown. Lymphocytic choriomeningitis virus (LCMV) infection of mice triggered potent cytotoxic activity of NK cells (NK^LCMV) against activated CD4 T cells, tumor cells, and allogeneic lymphocytes. In contrast, NK cells activated by vaccinia virus (VACV) infection (NK^VACV) exhibited weaker cytolytic activity against each of these target cells. Relative to NK^LCMV cells, NK^VACV cells exhibited a more immature (CD11b^-CD27⁺) phenotype, and lower expression levels of the activation marker CD69, cytotoxic effector molecules (perforin, granzyme B), and the transcription factor IRF4. NK^VACV cells expressed higher levels of the inhibitory molecule NKG2A than NK^LCMV cells. Consistent with this apparent lethargy, NK^VACV cells only weakly constrained VACV-specific CD4 T-cell responses. This suggests that NK cell regulation of adaptive immunity, while universal, may be limited with viruses that poorly activate NK cells.