Resveratrol (3,5,4'-trihydroxystilbene) is a natural component of certain foods, such as grapes, that has been shown to have anti-herpes simplex virus (HSV) activity in vitro. To determine if it is active in vivo, the abraded epidermis of SKH1 mice were infected with HSV-1 and topically treated with 12.5 or 25% resveratrol cream or cream only. Initial studies demonstrated that: (1). 25% resveratrol cream topically applied two, three, or five times a day effectively suppressed lesion development whereas 12.5% resveratrol cream effectively suppressed lesion formation when applied five times a day starting 1h after infection; (2). when treatment was begun 1, 6, or 12h after infection, both 12.5 and 25% resveratrol were effective at 1 and 6h after infection, but not if applied 12h after infection. Comparative studies between resveratrol cream, 10% docosanol cream (Abreva) and 5% acyclovir ointment (Zovirax) were also carried out. When treatment was begun 1h after infection and repeated every 3h five times a day for 5 days, 12.5 and 25% resveratrol significantly (P=0.0001) inhibited the development of HSV-1 induced skin lesions. Acyclovir was as effective (P=0.0001) as resveratrol. Animals that were topically treated with docosanol were not protected and developed lesions in a manner indistinguishable from cream only controls. These studies were repeated with an HSV-1 acyclovir-resistant virus. As before, 12.5 and 25% resveratrol cream effectively suppressed lesion formation. The skin of resveratrol-treated animals showed no apparent dermal toxicity such as erythema, scaling, crusting, lichenification, or excoriation. These studies demonstrate that topically applied resveratrol inhibits HSV lesion formation in the skin of mice.