In the present study we have examined the combined effect of HSV-1 inoculation and tobacco application (snuff water extract or smoking tar condensate) on the histopathologic changes of mouse labial mucosa. Two months' exposure to tobacco or HSV-1 inoculation alone did not induce dysplasia in the epithelium of labial mucosa, while HSV-1 inoculation combined with snuff water extract or smoking tar condensate produced epithelial dysplasia and other histomorphologic changes (that is, hyperkeratosis, increased granular cell layer thickness, acanthosis, and increased inflammatory cell infiltration in a significant number of animals). This result indicates that HSV-1 and tobacco could possibly act synergistically in the development of precancerous oral lesions and oral cancer.