The purpose of this investigation was to study the effect of snuff and experimentally induced herpes simplex virus type 1 (HSV-1) infection in Sprague-Dawley rats. It was demonstrated that it was possible to obtain 100% development of acute HSV-1 infection in the rat oral mucosa, but only 10% of latent reactive infection of the trigeminal ganglia. The rats were, therefore, acutely infected monthly with virus to simulate recurrence of latent infection. Virus was applied topically to the mucous membrane twice with an interval of one month. Snuff was administered between the virus applications and afterwards to half the virus-exposed animals. Sham-infected rats were given snuff during the same period (18 months). A fourth group of rats were left untreated. A complete post-mortem examination was performed. Two rats exposed to snuff and HSV-1 in combination developed squamous cell carcinoma of the oral cavity. It was also found that rats exposed to snuff alone or in combination with HSV-1 had a higher incidence of tumours or tumour-like conditions than control rats exposed to HSV-1 only. The incidence of malignant tumours was significantly higher in rats exposed to snuff or HSV-1 and snuff in combination than in control animals (p less than 0.05). The results of the study indicate that HSV-1 in combination with snuff exposure may be associated with the development of squamous cell carcinomas of the oral cavity.