To identify useful molecular markers for the treatment of head and neck cancers (HNCs), mutations of the TP53 and EGFR genes were analyzed in 56 HNCs, including 39 head and neck squamous cell carcinomas (HNSCCs). No EGFR mutation was observed in the fragments of exons 18-21. By contrast, 17 of 39 (44%) HNSCCs, as well as 3 of 6 cases (50%) with salivary gland carcinoma showed TP53 mutation in the fragments of exons 5-9. The incidence of nonsense mutation was 47%, which was higher than that in previous reports in other countries, suggesting the presence of etiological factors characteristic to Japanese patients. Further clinical assessment, including drug response and prognosis, is required in HNSCCs carrying the null-type mutation of TP53.