Ten renal smooth muscle tumors (seven leiomyomas, three leiomyosarcomas) and an unusual smooth muscle-invested renal cell carcinoma were studied for HMB-45 reactivity. All leiomyomas strongly expressed at least one, and most expressed three, smooth muscle markers (desmin, MSA, SMSA) and were negative for two cytokeratin markers (BDK, AE1). Six of seven leiomyomas and the smooth muscle investment of a renal carcinoma contained a population of cells strongly positive for HMB-45. A total of 15 blocks from the 6 HMB-45-positive leiomyomas were studied, and no adipocytes or abnormal vessels suggestive of angiomyolipoma were identified. The six HMB-45-positive leiomyomas seemed to arise from the renal capsule, whereas a seventh leiomyoma, which was negative for HMB-45, seemed to arise from the renal pelvis. Three leiomyosarcomas were also studied, which strongly expressed at least one smooth muscle marker and contained myofilaments at electron microscopic examination. No cytokeratin reactivity and no HMB-45-positive cells were detected in these leiomyosarcomas nor in the normal renal capsule adjacent to leiomyomas. This study showed that HMB-45-positive cells are detectable in a population of cells in some smooth muscle tumors, particularly in those that appear to arise from the renal capsule.