Mutations of the TP53 gene are the most common genetic alterations in human malignancies. Overexpression of the p53 protein has been reported in high frequencies in all types of skin cancer. To determine the role of TP53 in the pathogenesis of malignant melanoma, we investigated the expression of p53 in 12 cell lines and 145 primary and metastatic lesions by immunohistochemistry. Overexpression of p53 was predominantly detected in the cytoplasm of the cells in 96 (66%) tumor and 12 (93%) cell lines. In contrast to findings in other tumor types, in melanomas immunoreactive cells were found in clusters or as scattered single cells. In primary melanomas, the frequency of p53 overexpression did not correlate with tumor thickness. Nucleotide sequencing of TP53 genes of 24 melanoma tumors/cell lines demonstrated point mutations in seven samples, all coding for mutant p53 protein species. The frequency of TP53 alterations of 20%-30% is lower than in other skin tumor types. Notably, immunohistochemistry was not a suitable method to distinguish overexpression of wild-type p53 from mutant species, since cell lines/tumors with TP53 mutations did not show distinctive staining patterns. The mutation pattern in six out of seven lesions was similar to that caused by ultraviolet light damage. This finding may be regarded a further indication for a pathogenetic role of UV light damage in at least a subgroup of malignant melanomas.