Topical treatment with 3% phosphonoformate of herpes simplex virus type 1 (HSV)-induced skin infections of hairless mice reduced the severity of skin lesions when the treatment was initiated 3 hr after virus inoculation in the lumbosacral area or 3 and 24 hr after inoculation in the orofacial area. The mortality was significantly reduced in lumbosacral-infected mice and was completely prevented in orofacial-infected mice when the treatment was initiated with a delay of 24 hr after virus inoculation. However, phosphonoformate did not prevent the establishment of latent herpes simplex virus type 1 infections in the spinal and trigeminal ganglia, even when treatment was initiated as early as 3 hr after infection.