Recent reports have elucidated the variety of tissue types that can react with HMB-45. Consistent positivity has been demonstrated in angiomyolipomas, but only in the smooth-muscle cells. In this report, we examine five renal angiomyolipomas and 20 mesenchymal lesions with similar morphological features and with a possibly similar histogenesis. These include one retroperitoneal lymphangioleiomyomatosis, five epithelioid leiomyomas, nine leiomyosarcomas with epithelioid features, and five alveolar soft part sarcomas. HMB-45 demonstrated a strong diffuse cytoplasmic positive reaction with the smooth-muscle component in all cases of renal angiomyolipoma and in the one case of lymphangioleiomyomatosis. All alveolar soft part sarcomas, leiomyomas, and leiomyosarcomas were uniformly negatively stained by this antibody. We discuss the widening spectrum of lesions that are reactive with HMB-45 and the relationship of angiomyolipoma and lymphangioleiomyomatosis.