Over the last 22 years, we have encountered 34 examples of a highly aggressive neoplasm with a microscopic morphology that is highly predictive of finding sickled erythrocytes in the tissue. With the exception of one patient, all are believed to have had sickle cell trait or, in one case, hemoglobin SC disease. These 33 patients are the subject of this report and, where their race was known, they were all blacks between the ages of 11 and 39 years. Between the ages of 11 and 24 years, males predominated by 3 to 1. Beyond age 24, however, the tumors occurred equally in men and women. The dominant tumor mass was in the medulla and ranged from 4 to 12 cm in diameter. Mean size was 7 cm; median, 6 cm. Peripheral satellites in the renal cortex and pelvic soft tissues, as well as venous and lymphatic invasion, were usually present. The lesions exhibited a reticular, yolk sac-like, or adenoid cystic appearance, often with poorly differentiated areas in a highly desmoplastic stroma admixed with neutrophils and usually marginated by lymphocytes. The tumors had usually metastasized when first discovered, and none was confined to the kidney at the time of nephrectomy. The mean duration of life after surgery was 15 weeks. These tumors probably arise in the calyceal epithelium in or near the renal papillae, the same site that produces the more familiar picture of unilateral hematuria in patients with sickle cell trait. We have concluded that renal medullary carcinoma represents another example of renal disease associated with sickle cell disorders. The other six are unilateral hematuria, papillary necrosis, nephrotic syndrome, renal infarction, inability to concentrate urine, and pyelonephritis.