Sixty squamous cell carcinomas of tongue and buccal mucosa were examined for expression of p53 protein by using an immunohistochemical technique improved by an antigen retrieval method. Twenty-seven (45%) tumors demonstrated strongly positive staining. Thirteen of p53-positive tumors (48%) also exhibited overexpression of p53 in immediately adjoining hyperplastic or pre-malignant epithelium. All 22 metastatic lymph nodes and 18 local recurrent lesions (except two) had an identical p53 immunophenotype to their corresponding primary sites. Mitotic indices were significantly higher in p53-positive tumors (P < 0.01); however, no association of PCNA scores with p53 expression was found (P > 0.1). There was no correlation between p53 overexpression and tumor grade, size and staging, vascular invasion, lymph node metastasis, and early local recurrence. Overexpression of p53 was found to be relatively higher, although not statistically significant, in nonsmokers than in heavy smokers (66.7% vs. 42.9%), and in nonbetel-quid chewers than in heavy chewers (62.5% vs. 34.2%). These data are consistent with the hypothesis that inactivation of p53 protein may occur in the early phases of oral tumorigenesis. It may not be a useful prognostic marker but could possibly be used for risk assessment and surveillance of local recurrence.