Uterine leiomyomas are the most common tumor of the genitourinary system in women and are a major cause of morbidity. The molecular causes of the disease remain unclear. In this study, we examined gene expression in leiomyomas and normal myometrium. RNA was prepared and gene expression determined with the use of Affymetrix GeneChip U_95 arrays containing approximately 12,000 known genes and 48,000 expression sequence tags. Several genes were found to be differentially expressed in these two sample sets, and these genes were analyzed for their expression in a variety of other normal and diseased tissues. Four genes - doublecortin, calpain 6, interleukin-17B, and proteolipid protein 1 - were found to be overexpressed in leiomyomas compared with normal myometrium and eighteen other tissues. Sets of genes were identified whose expression could be used to cluster samples with leiomyomas or normal myometrium with the use of Eisen Cluster software. We conclude that differences in gene expression can be detected between leiomyomas and normal myometrium and that these changes in gene expression may yield clues to the pathophysiology of this common tumor.