The putative tumor suppressor gene p53 plays a key role in the regulation of cell proliferation. Functional loss of p53 protein through mutation or viral oncogene-complexing can result in p53 protein overexpression detectable by immunocytochemistry, which in turn has been associated with markers of poor prognosis in some cancers. We report here an analysis of p53 overexpression in fixed, embedded specimens from 81 prospectively collected head and neck tumors, both benign and malignant, including 55 squamous cell carcinomas, using monoclonal pAb1801. Sixty-two percent of the squamous cell carcinomas from the head and neck region overexpressed p53, whereas none of the benign tumors or adjacent normal tissues overexpressed p53. Overexpression of p53 was strongly associated (p < 0.01, two-tailed chi-square) with a histologic malignancy grading scale previously shown to have prognostic capabilities. We conclude that p53 overexpression is one of the most common abnormalities identified in head and neck cancer, and may be a useful marker in the study of multistep progression of tumorigenesis.