Congenitally athymic nude (nu/nu) mice of a BALB/c genetic background were found considerably more resistant to the induction of focal necrotic hepatitis by herpes simplex virus type 2 (HSV-2) tha, were phenotypically normal littermates (nu/+) or BALB/c mice. The augmented resistance was age dependent, as it was only manifested in mice from 4 to 5 weeks of age. Studies of the course of infection showed that nude mice were able to restrain virus multiplication in the liver far better than normal mice in the early phase of infection. However, they seemed inferior to normal mice in eliminating the infectious process. In vitro investigation of peritoneal macrophages revealed that macrophages from 6-week-old nude mice exhibited accelerated spreading and were three times as restrictive in the replication of HSV-2 as macrophages from normal mice. However, no difference was found in the efficiency of adsorption/phagocytosis between macrophages from nude and normal mice. The increased resistance of nude mice could be abolished by blockade of the microphage function of the mice by silica. Nude mice reconstituted at birth with thymus cells were just as susceptible to infection as normal mice. These data suggest that the increased resistance of nude mice to HSV-2 hepatitis is due to the presence of nonspecifically activated macrophages before infection.