Thrombomodulin (TM) is a surface glycoprotein reported to be expressed in a variety of tumors, including mesotheliomas, endothelial vascular tumors, squamous carcinomas, and various adenocarcinomas. This study evaluated TM expression in transitional cell carcinomas (TCCs) and determined whether immunostaining for TM has practical value in the diagnosis of TCCs. TM expression was observed in 96 of 106 primary tumors (bladder; 64/72; renal pelvis, 12/14; ureter; 3/3; prostate, 17/17) and in 21 of 23 metastatic TCCs. Among the adenocarcinomas, only 3 of 18 originating in the bladder 7 of 46 in the lung, 4 of 21 in the breast, 2 of 24 in the ovary, and 2 of 4 in the pancreas expressed this marker. No staining was observed in the 22 renal cell carcinomas or the 35 adenocarcinomas of the prostate, 23 of the endometrium, or 12 of the colon. Nearly all squamous cell carcinomas (lung, 21/27; skin, 7/7; uterine cen,ix, 6/6; esophagus, 2/2; bladder 2/2) reacted for TM. TM is a sensitive marker for TCC. TM immunostaining can assist in distinguishing this tumor from others, especially renal cell carcinomas and adenocarcinomas of the prostate, colon, and bladder; but it has no value in separating TCC from squamous cell carcinomas.