The observation that p53 alterations are early events in the tumorigenesis of head and neck cancer and the association with cigarette smoking have prompted us to search for p53 overexpression in the oral mucosa of heavy smokers who have no overt precancerous or cancerous lesions. Formalin-fixed paraffin embedded tissue sections, obtained from oral mucosa of 30 otherwise healthy heavy smokers, were evaluated for tobacco related changes, and immunostained with a mouse monoclonal antibody p53-DO7 for p53 immunoreactivity. Histopathological evaluation revealed hyperplastic changes in twenty eight samples (93%), eight of which also demonstrated dysplastic changes. Positive immunoreaction for p53 was detected in six (20%) of the tissue samples. The study provided significant information about the frequency of hyperplasia, dysplasia, and p53 overexpression in individuals who were heavy smokers. It is suggested, also, that chemoprevention might have some impact in this particular group of individuals.