Sensitivity to lethal infection with murine cytomegalovirus depends on the H-2 and background phenotype. H-2d appears to confer sensitivity in isolated cells, but sensitive BALB/c (H-2d) mice also exhibit non-specific immunosuppression which may indicate an impaired protective immune response. To determine the significance and mechanism of this immunosuppression, genetic factors controlling the activation, lymphocytostatic potential and accessory cell function of peritoneal macrophages were analysed after sub-lethal infection. In BALB/c mice, the number of peritoneal cells declined by 20% on day 3 post-infection and increased threefold over normal levels by day 7 with a progressive increase in macrophage activation and differentiation. Cells collected on day 7 exhibited lymphocytostatic activity which was not influenced by indomethacin and depressed their ability to act as accessory cells in a proliferative assay. Similar changes in the numbers of activated mature macrophages occurred in moderately resistant BALB.K (H-2k) mice showing an association with the background phenotype. In contrast peritoneal cell counts from resistant CBA (H-2k) mice were depressed by 80% on day 4 and the remaining cells enhanced the proliferation of syngeneic lymphocytes. However, later in the infection the percentage of peritoneal cells releasing virus declined rapidly and fewer cells became lymphocytostatic in both H-2k strains.