The objective of this study is to assess the expression of heat shock protein 105 (HSP105) in melanoma and benign melanocytic lesions. The expression of HSP105 in 62 human melanoma samples – 46 primary and 16 metastatic lesions – and 42 melanocytic naevi samples, was assessed by immunohistochemistry. Western blotting was performed on melanoma cell lines, melanoma tissues with matched normal skin and melanocytic naevi. The Mann–Whitney test was used for statistical analysis and significance was considered to be P less than 0.05. Seventy-four per cent of the primary melanoma lesions and 88% of the metastatic lesions overexpressed HSP105 by immunohistochemistry. The majority of melanocytic lesions (95%) were negative (P<0.05). Western blotting detected high expression of HSP105 in melanoma cell lines and tissues. The expression of HSP105 was related to the invasiveness of the lesions. Melanocytic naevi expressed HSP105 at a level that was similar to that of normal skin. Our results show that high expression of HSP105 is associated with malignant melanoma especially advanced and metastatic lesions. The results suggest that HSP105 analysis may be a helpful tool as a poor prognostic indicator and as a diagnostic aid in problematic lesions; in addition, melanoma can be included in the growing list of tumours overexpressing HSP105 to be targeted for potential HSP105-based therapeutic strategies.