In vitro, T cell‐dependent cytotoxicity is mediated by two distinct mechanisms, one being perforin‐, the other Fas‐dependent. The contribution of both of these mechanisms to clearance of viral infections was investigated in mice for the noncytopathic lymphocytic choriomeningitis virus (LCMV) and the cytopathic vaccinia, vesicular stomatitis (VSV) and Semliki forest (SFV) viruses. Clearance of an acute LCMV infection was mediated by the perforin‐dependent mechanism without measurable involvement of the Fas‐dependent pathway. For the resolution of vaccinia virus infection and for resistance against VSV and SFV, however, neither of the two pathways was required. These data suggest that perforin‐dependent cytotoxicity mediated by T cells is crucial for protection against noncytopathic viruses, whereas infections with cytopathic viruses are controlled by nonlytic T cell‐dependent soluble mediators such as cytokines (IFN‐γ against vaccinia virus) and neutralizing antibodies (against VSV and SFV).