Infections by herpes simplex virus (HSV) cannot yet be eliminated, but the severity of the disease can be reduced. Two newer drugs with established efficacy for such infections, famciclovir and valacyclovir, were tested in a mouse eye model of HSV infection. Both drugs significantly reduced mortality and titers of virus shed from the eyes of mice infected with an otherwise lethal dose of HSV type 1 (HSV-1). Similar titers of HSV-1 were found in the eyes, ganglia, and brains of treated animals. Although valacyclovir reduced the latent viral DNA load better in these studies than did famciclovir, rates of reactivation by explantation and UV exposure were the same. Thus, in this study, famciclovir and valacyclovir were equally effective in limiting the virulence and spread of HSV-1, despite their biochemical and pharmacologic differences.