P53 mutations are currently recognized as the most common genetic alteration in human tumors. The purpose of our study was to evaluate the significance and reliability of p53 genotyping in head and neck cancer as a possible marker permitting the prediction of tumor behavior and clinical outcome. P53 genotyping in our study refers to highly sensitive molecular screening in order to detect structural alterations in the nucleic acid sequence of the gene. Exons 2-11 and adjacent intronic regions were screened for mutations by direct genomic sequencing or by bi-directional dideoxyfingerprinting in 66 primary tumors of the larynx, pharynx and oral cavity. Alterations in the <hot spot region> of the p53 gene were detected in 36% (24 of 66) of the analyzed tumors, no mutation was found in our cohort outside exons 5-8. The frequency of p53 mutation had no correlation to the tumor stage or tumor site. The recurrence rate in patients with a p53 alteration was not significantly higher compared to patients without a p53 mutation in their primary tumors. Summarizing the results of our study only limited reliability of p53 genotyping as an effective concept for molecular testing of head and neck cancer was found.