Despite the steadily increasing number of patients suffering from squamous-cell carcinomas of the oropharyngeal region, little is known about the molecular steps involved in the induction of these neoplasms. We investigated oropharyngeal cancers from 38 patients for mutations in the p53 tumour-suppressor gene. The majority of patients (74%) had a history of tobacco and alcohol abuse. Five had lymph-node metastases, 3 had multiple primary carcinomas and 2 presented with multiple primary tumours and lymph-node metastases. Exons 5 through 8 of the p53 gene were screened by single-strand conformation polymorphism analysis followed by direct DNA sequencing. A total of 16 tumours (42%) contained point mutations which were scattered throughout exons 5 to 8. Most mutations (56%) were transitions, predominantly G-->A. Among the transversions, G-->T mutations prevailed; these have also been found in smoking-related lung cancer. One carcinoma of the soft palate showed a mutation which was retained in a lymph-node metastasis. In another patient, 2 primary carcinomas had different mutations, indicating that they had developed independently. Similar results were obtained in a case with a p53 mutation in the third of 3 primary tongue carcinomas which developed over a period of 23 years. One lymph-node metastasis had a 12-bp deletion which was not detected in any of the primary malignancies. The frequent occurrence of p53 mutations in oropharyngeal carcinomas supports the view that they play a role in the initiation or progression of the malignant phenotype.