Purpose: Head and neck squamous cell carcinomas (HNSCC) are the most frequent malignancies of the upper aerodigestive tract. Cisplatin resistance is a major problem in the treatment of a large number of HNSCC cancer patients. In this study, nine randomly selected HNSCC cell lines were investigated regarding expression, presence of mutations, nucleocytoplasmic distribution of p53, and sensitivity to cisplatin. Experimental Design: Protein expression was evaluated by Western blot analysis. The whole open reading frame of p53 was determined by reverse transcription-PCR sequencing. Nucleocytoplasmic distribution was evaluated by confocal laser scanning microscopy. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay was used to test for cisplatin sensitivity. Results: p53 mutations were found in all nine investigated HNSCC cell lines. Nuclear p53 signal was detected in six cell lines, whereas three cell lines exhibited total loss of nuclear p53 signal. Nuclear signal depended on the presence or absence of the COOH-terminal nuclear localization signal in p53. Cisplatin sensitivity was highly reduced in the group with loss of nuclear p53 signal compared with those with detectable nuclear signal. Transfection of wild-type and mutant p53 into a rat embryonic cell system showed highly reduced activity of the nuclear localization signal mutant p53 protein.Conclusion: Taken together, these data suggest that ''loss of nuclear p53 signal''correlates with cisplatin resistance in HNSCC. If these results can be validated on a larger number of tumor samples, including fresh tumor tissues, it potentially could help in sparing a subgroup of HNSCC patients the side effects associated with unnecessary chemotherapy by identifying cisplatin nonresponders before chemotherapy induction. Head and neck squamous cell carcinomas (HNSCC) accountfor the vast majority (>90%) of malignancies found in the upper aerodigestive tract. They are characterized by their early predominantly lymphatic metastatic spread (1, 2). For over 30 years now, there was no significant improvement of the patient survival time regardless of new developments in surgical techniques as well as in the chemo(radio)therapy treatment scheme of this tumor entity. Despite successful surgical removal of the primary tumor, which can be achieved in most cases, a high number of patients already developed regional lymph node or distant metastases at the time of diagnosis. The treatment scheme of this head and neck cancer, therefore, frequently includes additional surgery to remove tumorrelated lymph nodes (neck dissection) and postoperative chemo(radio)therapy or in the case surgery is not possible because of advanced tumor stage for example, primary chemo(radio)therapy. Postoperative survival of patients with regional lymph node or distant metastases then largely depends on the success of chemo(radio)therapy. Frequently, however, patients relapse after chemo(radio)therapy. Then, after having exhausted the full dose of local radiotherapy, chemo...