Weanling ICR Swiss mice were inoculated intranasally with a lethal dose of herpes simplex virus type 2, and treated with either vidarabine, vidarabine-5'-monophosphate, acyclovir or a hybrid recombinant human alpha interferon which is active in murine tissues. Treatment with antiviral drugs was initiated 2, 24, 48, 72 or 96 h following virus inoculation. Single drug treatment showed little effect on mortality, with only acyclovir showing some slight reduction. Four dual drug combinations (vidarabine/acyclovir; vidarabine/interferon; vidarabine 5'-monophosphate/acyclovir and vidarabine 5'-monophosphate/interferon) were all associated with marked reductions of mortality when treatment was begun at 2 h, and this beneficial effect increased further when therapy was delayed until 24 or 48 h following virus inoculation. However, the combination of acyclovir/interferon was consistently toxic to the mice, unless a reduction in dosages was employed. These results suggest that certain antiviral combinations might be useful for serious human infections caused by herpes simplex virus.