Malignant transformation is thought to be associated with changes in the expression of a number of genes, and this alteration in gene expression is considered critical to the development of the malignant phenotype. In this study, gene expression in 8 samples of giant-cell tumor (GCT) of bone, as well as in bone at the site of osteoarthritis and in a variety of normal tissues, was determined at Gene Logic Inc (Gaithersburg, Md) with the use of Affymetrix GeneChip ® U_133 arrays containing approximately 40,000 genes/expressed sequence tags (ESTs). Gene-expression analysis was performed with the use of the Gene Logic GeneExpress ® Software System. Differences in gene expression between GCTs and bone were observed. In addition, genes expressed uniquely in GCTs among these and 519 samples from 20 other tissue types were identified. Some of the genes that were found to be overexpressed in GCTs, such as tartrate-resistant acid phosphatase and the lysosomal H +-transporting ATPase, are also expressed by osteoclasts. Osteoprotegrin ligand (OPGL) was also selectively overexpressed in GCTs. The genes found to be overexpressed in GCTs appear to reflect the genetic profile of osteoclast-lineage cells and also the genetic profile of an osteoclastogenic environment. The genes identified in this study may play a role in the pathogenesis of GCTs, confirm the likely importance of OPGL in GCT pathogenesis, and may indicate other possible targets to which antitumor therapy could be directed.