An immunohistochemical study of primary oral squamous cell carcinomas (n = 37) with a monoclonal antibody (PAb 1801) specific to p53 antioncogene product demonstrated nuclear overexpression of the mutant protein in 35% of cases. Those positive included carcinomas without deep invasion suggesting that p53 mutation may occur in the early stages of progression of a malignancy. This is supported by the observation that mutant protein was detectable in limited amounts in 2 cases of oral mucosal dysplasia (n = 12). None of the normal or reactive oral mucosal tissues (n = 17) were positive for p53. The presence or absence of p53 was not correlated with the site of the lesion or its degree of differentiation. Our data suggest that p53 gene mutations are commonly involved in oral cancer but are neither sufficient nor necessary for the development of malignancy. Nevertheless, as this mutation is the commonest genetic change described so far in cancers in white caucasoids, it is possible that its presence can be used as a marker of risk in a high proportion of malignant and potentially malignant oral lesions.