The significance of the natural killer (NK) cell response to murine cytomegalovirus (MCMV) infection was evaluated in C3H/HeN mice. This strain was selected for study after preliminary demonstration that the NK cell response, occurring between 3 and 6 days post-infection was relatively high in comparison to other mouse strains studied. A dose-response effect of hydrocortisone treatment on suppression of this response was found. A dose of hydrocortisone, given subcutaneously on two successive days, which was found to markedly inhibit the NK cell response, had no effect on development of serum interferon or antibody levels, or spleen cytotoxic T cell activity under the conditions studied. Suppression of the NK cell response by this treatment, however, was accompanied by enhanced spleen and pulmonary virus replication in vivo and increased susceptibility of mice to lethal infection. MCMV interstitial pneumonitis was characterized histologically and lung lymphocytes studied at 4 days post-infection were found to have increased NK cell activity. Treatment of mice with hydrocortisone was found to inhibit development of gross and histological evidence of pneumonitis. These findings indicate that NK cells are involved in the pathogenesis of MCMV interstitial pneumonitis and may function early in infection to restrict the extent of virus replication.