Virus-specific cytotoxic T lymphocytes (CTL) mediate their antiviral activity either by direct lysis of infected cells, or by the release of soluble lymphokines, or by a combination of the two. We have examined the role played by interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF alpha) in virus clearance. In vitro the amount of IFN-gamma synthesized by some lymphocytic choriomeningitis virus-specific H-2-restricted CTL clones was quantitatively too small to correlate with a direct antiviral activity in vivo. However, treatment of mice with a neutralizing monoclonal antibody to IFN-gamma significantly inhibited the clearance of virus from the spleens of acutely infected mice given adoptive transfers of immune spleen cells. Additionally, mice treated with exogenous recombinant murine IFN-gamma 24 h before or at the same time as virus inoculation showed reduced virus titres in their spleens. Hence, IFN-gamma displayed a direct antiviral effect in vivo. In contrast, treatment of mice with recombinant TNF alpha had no effect on virus clearance and thus TNF alpha is unlikely to play a significant role in this acute viral infection.