The host-mediated antiviral effect of N alpha-(N-acetylmuramyl-L-alanyl-D-isoglutaminyl)-N epsilon-stearoyl-L-lysine [MDP-Lys(L18)] was evaluated in mice against murine cytomegalovirus (MCMV) infection. Mice treated with 800 micrograms of MDP-Lys(L18) on day 2 before the virus challenge survived systemic lethal infection. The protective effect of MDP-Lys(L18) was evidenced by an increase in plaque-forming units per LD50 and a decrease in virus titers in the target organs. No significant difference in the serum interferon level and 2',5'-oligoadenylate synthetase activity was observed among the mice treated with test compounds or phosphate-buffered saline, thought they were higher in MCMV-infected mice than in mock-infected mice. The natural killer (NK) activity was augmented remarkably in the mice treated with MDP-Lys(L18) or its original component, muramyldipeptide (MDP). MDP-Lys(L18) showed neither virocidal nor virostatic activity on MCMV in vitro. Thus, MDP-Lys(L18)-induced resistance against MCMV infection seems to be host-mediated. The MDP-Lys(L18)-induced resistance was not abrogated by the treatment with anti-asialo GM1 serum. The NK activity augmented by MDP-Lys(L18) may contribute to some part of the protective effect, though the augmentation of the NK activity alone did not correlate completely with the protective effect of MDP-Lys(L18). In addition, no difference was observed in anti-MCMV activity among peritoneal exudate cells from mice treated with MDP-Lys(L18), MDP or phosphate-buffered saline. Therefore, another host-mediated factor(s) may also participate in the antiviral effect of MDP-Lys(L18).