Homeobox-containing genes comprise a gene family coding for transcription factors involved in normal development. Class I human homeobox (HOX) genes display a peculiar chromosomal organization, perhaps directly related to their function. Aberrant expression of homeobox genes has been associated with both morphological abnormalities and oncogenesis. We have reported that HOX gene expression is (i) specific for normal adult human organs (kidney, colon, lung) and (ii) altered in cancer specimens according to their histological type and stage of tumor progression. Here, we have investigated whether patterns of HOX gene expression are associated with tumor heterogeneity by analyzing the expression of the entire panel of 38 HOX genes in clones isolated from a single human metastatic melanoma call line (Me 665/2). The differential expression of a block of genes located at the 5' end of the HOX C locus allows melanoma clones to be classified into 2 major groups. The 2 patterns of HOX gene expression are inversely associated with 2 distinct surface phenotypes for integrins (VLA-2, VLA-5 and VLA-6) and the adhesion molecule ICAM-1. The genes of the HOX C locus are silent in the clones with high levels of integrins VLA-2, VLA-5 and VLA-6 and of the adhesion molecule ICAM-1 but actively expressed in the clones with low levels of ICAM-1 and lacking VLA-2, VLA-5 and VLA-6. Our results indicate that HOX gene expression reflects the intra-tumor heterogeneity of melanoma clones and suggest that the expression of surface molecules involved in cell-cell and cell-matrix interactions may be related to the patterns of HOX gene expression.