The host-mediated antiviral effect of Chlorella vulgaris extracts (CVE) was evaluated in ICR mice against murine cytomegalovirus (MCMV) infection. Mice treated with 10 mg of CVE on days 3 and 1 before virus challenge survived lethal infection. The protective effect of CVE was shown by a decrease in the infectious viruses replicated in the target organs of CVE-treated ICR mice. CVE also protected mice from histopathological damage to the target organs due to MCMV infection. Both the serum interferon (IFN) level and 2'5'-oligoadenylate (2-5A) synthetase activity were elevated in CVE-treated and MCMV-infected mice, and were higher than those in the control mice. The natural killer (NK) activity of spleen cells, which is otherwise deteriorated by lethal MCMV infection, was remarkably augmented in CVE-treated mice. Neither virocidal nor virostatic activity of CVE on MCMV was seen in vitro. Thus, CVE-induced resistance against MCMV seems to be host-mediated. The protective effect correlated with the augmentation of NK activity of the spleen cells and serum IFN activity, which inhibited replication of MCMV in the target organs and subsequently saved the mice from death.