Previous studies indicate that the nonclassical class I HLA-G antigen, whose physiologic expression is mainly restricted to placenta, is upregulated in melanoma, renal carcinoma, lung carcinoma, glioblastoma and ovarian carcinoma, where its inhibitory effect on cytotoxic effector cells function is thought to participate in immune evasion by tumor cells. To define whether this expression was a specific feature of melanocytic malignant transformation, 174 paraffin-embedded melanocytic lesions including naevi, lentigo, primary and metastatic melanomas were analyzed for HLA-G and other HLA class I and class II antigen expression. HLA-G antigen expression in melanocytic cells was found to be significantly higher (p < 0.0003) in melanoma (22/79, 28%) than in naevi (1/70, 1.4%), suggesting that upregulation of HLA-G is associated with malignant transformation in this cell type. Further identification of HLA-G antigen expression in inflammatory infiltrating cells results in an overall frequency of HLA-G expressing cells that is higher in melanoma (28/79, 35.5%) than in naevi (5/60, 8.3%) or lentigo (2/23, 8.7%). Upregulation of HLA-G or HLA class II molecules in melanocytic cells thus appears as a better predictor of malignancy than classical HLA class I antigen defects, which are often described as an important mechanism used by tumor cells to evade immune surveillance. Furthermore, HLA-G expression was electively found in lesions that exhibited a high inflammatory infiltrate as well as in patients displaying HLA-A1 genotype. These findings may provide new insights in the comprehension of tumor progression and design of therapeutic approaches aimed at enhancing antitumor immune responses in melanoma patients. © 2003 Wiley-Liss, Inc.