To investigate the pathologic, clinical, and genetic features of renal medullary carcinomas (RMCs) in search of clues to their pathogenesis. We analyzed 40 RMCs for clinical features, for immunohistochemical expression using a panel of markers, and for genetic changes using comparative genomic hybridization. Patients presented at 5 to 32 years of age, and 82% were African American. All patients tested had sickle cell trait or disease. Seven patients presented with suspected renal abscess or urinary track infection without a clinically recognizable mass. Of the 15 tumors able to be analyzed, all were positive for epithelial markers CAM 5.2 and epithelial membrane antigen. All were negative for high-molecular-weight cytokeratin 34betaE12. Cytokeratins 7 and 20 and carcinoembryonic antigen were heterogeneous and variable. Ulex was focally positive in a minority of cases. Eight of 12 tumors showed significant positivity for TP53 protein (greater than 25% nuclear positivity). All tumor tested (n = 8) were strongly positive for vascular endothelial growth factor and hypoxia inducible factor. Of nine tumors analyzed for genetic gains and losses using comparative genomic hybridization, eight showed no changes and one showed loss of chromosome 22. Survival ranged from 2 weeks to 15 months (mean 4 months). These findings suggest that RMC is clinically and pathologically distinct from collecting duct carcinoma. The hypothesis that chronic medullary hypoxia secondary to hemoglobinopathy may be involved in the pathogenesis of RMC is suggested by strong vascular endothelial growth factor and hypoxia inducible factor expression and positivity for TP53.