Inbred mouse strains differ in susceptibility to infection with herpes simplex virus type 1 or type 2 (HSV-1, HSV-2). In this study interferon production was tested in the peritoneal exudate of mice after intraperitoneal (i.p.) injection of HSV-1 or HSV-2. In HSV-resistant mice (C57 BL/6, C3 H/HeJ) high titers of interferon were already present 2 to 4 hours after injection. In comparison, less resistant mice (DBA/2, AKR) lacked this early response. There was no correlation between interferon titers and resistance at post-infection times later than twelve hours. At twelve hours, however, high titers of HSV were detected in the peritoneum of DBA/2 mice and significantly lower titers in C57 BL/6 mice. In a comparative analysis of eight different inbred mouse strains, again early (2 to 4 hours) interferon production was correlated to resistance. In assays of HSV-stimulated early (24 hours) NK cell responses not only the good interferon producer strains but also one of the less resistant low interferon producers (BALB/c) showed significant cytotoxic activities. Conversely, SJL mice that are very low in HSV-induced NK cell activity are resistant and show high early interferon responses at the local site.