The relative therapeutic effects of vidarabine (9-β-D-arabinofuranosyladenine), cyclaradine (the adenosine deaminase-resistant carbocyclic analog of vidarabine), and cyclaradine-5'-methoxyacetate in the parenteral treatment of systemic herpes simplex virus type 1 infections in Swiss mice were determined. Among control mice inoculated intraperitoneally with virus, a mortality rate of 95% was observed. The intraperitoneal administration of nontoxic doses of vidarabine (125 to 250 mg/kg per day) or cyclaradine (113 to 450 mg/kg per day), by daily injections for 7 days beginning 4 h after virus inoculation, reduced mortality to 0 to 10%. Among control animals inoculated intracerebrally with 32 50% lethal doses of virus, 100% mortality was observed, with a mean survival time of 4.6 days. Treatment with either drug at equimolar dose levels ranging from ca. 32 to 750 mg/kg per day produced significant (P < 0.0005), dose-dependent increases in the mean survival time of animals dying of herpesvirus encephalitis. Mice inoculated intracerebrally with 10 50% lethal doses of virus exhibited 97% mortality and a mean survival time of 5.5 to 6.4 days. Treatment with vidarabine, cyclaradine, or cyclaradine-5'-methoxyacetate significantly increased the mean survival time of dying animals and, at doses ranging from 250 to 750 mg/kg per day, produced significant increases in survival. The three drugs displayed equivalent antiviral efficacy in vivo. Drug toxicity (measured by weight loss) was not detected in mice treated with cyclaradine or cyclaradine-5'-methoxyacetate at 750 mg/kg per day, whereas severe toxicity (weight loss of ≥3 g) was observed in mice treated with vidarabine at an equivalent dose level. Thus, cyclaradine or its 5'-methoxyacetic acid ester may possess some advantage over vidarabine in the treatment of severe herpesvirus infections and should therefore be considered for clinical trials in humans.