We studied the expression of cytokeratin (CK)-7 and CK-20 in prostate adenocarcinoma and urothelial carcinoma and evaluated their usefulness for distinguishing high-grade forms of these tumors. We examined prostate adenocarcinoma in 59 radical prostatectomy specimens and in 10 autopsy specimens showing metastatic disease, and urothelial carcinoma of the bladder in 28 cystectomy specimens. Immunohistochemical staining for CK-7, CK-20, and prostate-specific antigen (PSA) was performed on paraffin sections. For prostate adenocarcinoma, 5 cases had only CK-7 positivity, 5 had only CK-20 focal positivity, 1 stained for both markers, and 48 were negative for both. PSA was positive in all but 1 poorly differentiated prostatic carcinoma. In the autopsy cases, PSA was expressed in the prostate and the metastatic tumors in most cases; few cases were focally positive for CK-7 or CK-20, but none was positive for both markers. For the urothelial tumors, CK-7 was the sole positive marker in 6 cases, and CK-20 in 1 case; 17 cases were positive for both, and 4 were negative for both. All urothelial carcinomas were PSA negative. Although PSA is useful for differentiating prostatic from urothelial carcinoma, CK-7 and CK-20 are helpful when both are positive, supporting the diagnosis of urothelial carcinoma. However, if only 1 marker is positive or both are negative, these markers have limited usefulness for distinguishing these carcinomas.