A number of epidemiologic studies indicate that snuff dipping is associated with an increased incidence of oral cancer in human beings. Since inactivated herpes simplex virus (HSV) has been shown to induce malignant changes in vitro and in vivo and is partially inactivated by snuff water extract, we examined the histopathologic changes of hamster buccal pouches after exposure to repeated HSV inoculation combined with long-term simulated snuff dipping. One hundred twenty-five Syrian hamsters were divided into seven groups, and the buccal pouches were inoculated with HSV-1, HSV-2, or culture medium. The mock and HSV inoculations were done once a month for 6 consecutive months. In an effort to determine the effect of snuff on the mock- or HSV-inoculated buccal pouches, a consistent amount of a commercially available snuff was placed into both the right and left pouches twice a day in half of the animals. At the end of the 6 months of simulated snuff dipping (4 weeks after the final mock or viral inoculation), the hamsters were killed and the buccal pouches were removed for the histopathologic evaluation. Neither simulated snuff dipping nor HSV infection alone induced neoplastic changes in hamster buccal pouches. However, HSV infection in combination with simulated snuff dipping resulted in epithelial dysplasia and invasive squamous cell carcinoma in more than 50% of the animals.