Multimodal therapy of oral squamous cell carcinomas today is based on surgery, radiotherapy and chemotherapy. Despite the combination of all three therapeutic options, there is still a large number of treatment failures and therefore major questions remain. Recent investigations suggest that mutations of the p53 tumor suppressor gene may account for some of the therapeutic failures. Inactivation of the gene may be an important determinant of the efficacy of today's multimodal therapy protocols. In 90 patients with squamous cell carcinomas of the oral cavity biopsy specimens were taken before and after preoperative radiochemotherapy. From all patients, biopsy and resection material was available for immunohistochemical analysis of p53. After radiation treatment, 51 patients (57%) showed a complete response; 39 patients (43%) only showed a partial response or did not respond at all. Among the responders, 82% of the pretherapeutic tumors were p53 positive, whereas among the nonresponders only 56% of the pretherapeutic tumors were p53 positive. The majority of the residual tumors were also p53 negative according to immunohistology after radiation treatment. In our study, detection of p53 protein by immunohistochemistry seemed to be connected with a more radiosensitive reaction of the tumors. Nevertheless, successful strategies for radiation therapy may need to take into account the tissue of origin and the status of p53 in the tumor.