BACKGROUND The differentiation of epithelial tumors arising in the kidney (urothelial vs. renal cell carcinoma) sometimes can be difficult by clinical and radiologic studies. Because urothelial and renal epithelium express unique cytokeratin (CK) 7 and 20 profiles, the authors studied the utility of these markers to confirm the diagnosis of urothelial carcinomas that present clinically as kidney masses. METHODS Using commercially available monoclonal antibodies, paraffin section immunohistochemistry was used to examine two recent cases of urothelial carcinomas presenting as renal tumors. Tissues were stained for CK7 and CK20 and the expression compared between the tumor and benign tissue. RESULTS Both cases showed solid renal masses that clinically and radiographically could have been of renal cell origin, but subsequently were confirmed histologically to be extensive renal involvement by urothelial carcinoma. The tumors coexpressed both CK7 and CK20, which is the expected profile for carcinomas of urothelial but not renal origin. CONCLUSIONS The results of the current study show that coexpression of CK7 and CK20 is a useful diagnostic aid in the differential diagnosis of epithelial kidney tumors of urothelial cell versus renal cell origin.