New Zealand white rabbits less than 30 h old were inoculated subcutaneously with 10(3) 50% tissue culture infectious doses of type 2 herpes simplex virus. The animals were randomly assigned to a treatment schedule of daily intraperitoneal injections of acyclovir, beginning on the day of virus inoculation for 6 or 12 days, on post-inoculation day 1 for 6 days, or on post-inoculation day 2 for 6 days. The acyclovir was given in doses of 50 mg/kg of body weight per day. Similarly infected animals receiving daily intraperitoneal injection of Eagle minimum essential medium served as controls. All of the control animals died on day 4 or 5 after inoculation. At death they exhibited severe skin lesions, viremia, and dissemination of virus in various visceral organs and spinal as well as trigeminal ganglia. In contrast, animals treated with acyclovir failed to develop significant skin lesions, and death did not occur while treatment continued. Termination of treatment after 6 days resulted in late-onset fatal disease and virus isolation from the brain in many rabbits regardless of the treatment schedule. No such late fatality was observed and no virus could be detected from the brain when treatment was initiated on the day of virus inoculation and continued for 12 consecutive days. With respect to all of the variables studied, treatment for 12 days beginning on the day of virus inoculation was most effective.