Natural killer (NK) cell-depleted or control mice were treated prophylactically with polyinosinic: polycytidylic acid (polyI: polyC) or purified beta interferon (IFN) and then infected with either vaccinia virus or murine cytomegalovirus. NK cell depletion alone enhanced virus titres in the spleen and peritoneal cavity. However, poly I: polyC and IFN inhibited virus replication equally well in control and NK cell-depleted mice. This suggests that prophylactic IFN treatment mediates antiviral effects independently of NK cells.