Mutation of the tumor suppressor gene p53 is the most frequent genetic alteration of human tumors. Our systematic immunohistochemical analysis of the p53 phenotype and the comparison to proliferation and differentiation has revealed that over 50% of the squamous cell carcinomas of the head and neck show p53 accumulation of aberrant p53 protein. Normal epithelia did not show p53 accumulation and benign lesions only in exceptional cases. Expression of aberrant p53 was invariably confined to dysplastic cells in close vicinity to the tumor and to invasive, dedifferentiated tumor cells with high proliferative potential, as revealed by expression of the histone H3 gene and of the simple epithelial type cytokeratins. We discuss the possible clinical value of the immunohistochemical screening of tumor patients for the status of the p53 gene.