Representational difference analysis was used to identify genes that are expressed in a human melanoma cell line and not in normal skin. A cDNA clone that appeared to be specific for tumors was obtained and the corresponding gene was sequenced. This new gene was named LAGE-1. Using a LAGE-1 probe to screen a cDNA library from the same melanoma cell line, we identified a closely related gene, which proved to be identical to NY-ESO-1, a gene recently reported to code for an antigen recognized by autologous antibodies in an esophageal squamous cell carcinoma. Gene LAGE-1 maps to Xq28. It comprises 3 exons. Alternative splicing produces 2 major transcripts encoding polypeptides of 210 and 180 residues, respectively. Expression of LAGE-1 was observed in 25–50% of tumor samples of melanomas, non-small-cell lung carcinomas, bladder, prostate and head and neck cancers. The only normal tissue that expressed the gene was testis. As for MAGE-A1, expression of LAGE-1 is induced by deoxy-azacytidine in lymphoblastoid cells, suggesting that tumoral expression is due to demethylation. The expression of LAGE-1 is strongly correlated with that of NY-ESO-1. It is also clearly correlated with the expression of MAGE genes. Int. J. Cancer 76:903–908, 1998.© 1998 Wiley-Liss, Inc.