Inoculation of herpes simplex virus on the forehead and/or snout of hairless mice resulted in a significantly lower mortality rate than inoculation of the skin in the lumbosacral area. Latent herpes simplex virus infections were detected in all forehead-inoculated and in 90% of snout-inoculated mice. Phosphonoacetic acid was highly effective in preventing the development of skin lesions, and no latent infections were detected when phosphonoacetic acid ointment was applied 3 h after infection. Neither adenine arabinoside nor adenine arabinoside monophosphate prevented the establishment of latent infections in the trigeminal ganglia, although they protected the mice from the fatal outcome of the infection. The antibody response after adenine arabinoside or adenine arabinoside monophosphate treatment was similar to that observed in untreated animals, and it was six to eight times higher than in mice treated with phosphonoacetic acid. Mice without evidence of latent infection had, in general, lower serum antibody titers than those with latent infections in the ganglia. An analysis of the pathogenesis of herpes simplex virus infection in mice treated with adenine arabinoside showed that virus penetration into the nerve endings was delayed and that the amount of free virus in ganglionic homogenates was 10 to 100 times less than that for untreated mice.