We used suppression subtractive hybridization to identify highly expressed genes in the cancerous region of human renal cell carcinoma (RCC) compared with noncancerous tissue. Nine genes were identified to show increased expression in the cancerous region compared with the noncancerous region. The nine genes included thymosin beta4, secreted protein acidic and rich in cysteine (SPARC), Cap43, ceruloplasmin, serum amyloid A, osteopontin, heat shock protein 90 (HSP90), LOT1, and casein kinase I. Of these 9 genes, in situ hybridization with 10 clinical samples consistently showed a strong expression of Cap43 mRNA in infiltrating macrophages in RCCs, but not in cancer cells proliferating in an alveolar pattern. However, Cap43 mRNA was also apparently detected in epithelial cells of the renal proximal tubuli in noncancerous tissue. The higher expression of the Cap43 gene in the cancerous region of RCCs appears to depend on macrophage infiltration. Moreover, treatment with phorbol ester resulted in enhanced expression of the Cap43 gene in human monocytic cells in vitro. The expression of the Cap43 gene in infiltrating macrophages is discussed in association with the differentiated or activated status of monocyte/macrophage.