The nucleoside analog acyclovir [9-(2-hydroxyethoxymethyl)guanine] and the hybrid recombinant human alpha interferon (rHuIFN-alpha A/D) were evaluated in weanling mice for their efficacy alone and in combination against a lethal systemic infection with herpes simplex virus type 1. Simultaneous parenteral treatment with combinations of both agents at various doses resulted in a higher percentage of survival than when either agent was administered alone, with a synergistic interaction demonstrated at certain dose combinations. Sequential administration of parenteral rHuIFN-alpha A/D and oral acyclovir, administered by gavage or supplied ad libitum in drinking water, resulted in a synergistic interaction at all dose combinations tested. These results suggest that combinations of interferon and acyclovir may be useful in treating primary herpes simplex virus infections in humans.