Tamm-Horsfall protein (THP) is a high-molecular-weight glycoprotein synthesized exclusively by the ascending loop of Henle and the distal tubule of normal kidney. In pathologic conditions, THP may accumulate in renal parenchyma, perirenal soft tissue, or renal hilar lymph nodes. Our recent finding of a cystectomy specimen showing large mural deposits of THP prompted a pertinent literature search, which uncovered only a single article in which THP deposition in bladder is briefly mentioned. In the current study, the clinical and morphologic features of THP were studied in 247 consecutive bladder biopsies and 15 cystectomies obtained in a 1-year period. A total of 18 cases were found (an incidence of 6.9%), with cystectomy specimens being much more frequently affected than biopsy specimens (60 versus 3.6%). Most patients were elderly men (45-78 years, with a mean 61 years; a male/female ratio of 16:2). In seven cases, THP appeared as large, "waxy," pale or weakly eosinophilic masses, so characteristic that the diagnosis could be readily made without any special studies. THP in these cases was strongly positive by periodic acid-Schiff, pale blue on Masson's trichrome stain, and ultrastructurally composed of nonbranching 4-nm-wide fibrils arranged in a parallel fashion. In 11 cases, THP appeared as inconspicuous flecks or interconnecting strands of eosinophilic material obscured by a large amount of adjacent fibrinous exudate or necrotic tissue. In these cases, the PAS and trichrome stains were not always helpful in the diagnosis. Immunostaining using an anti-THP antibody clearly identified even small amounts of THP in all 18 cases. This immunostaining was not only sensitive but also specific, giving a negative result for 64 control cases containing such materials as amyloid, fibrin, dense fibrosis, tissue necrosis, and edema fluid, all of which can potentially simulate THP. Although diagnoses for the specimens with THP were variable (nine transitional cell carcinomas, one squamous cell carcinoma, two nephrogenic adenomas, and five cases of cystitis), the areas where THP was deposited in each of these cases invariably showed necrosis, inflammation, fibrinous exudate, ulcer, or crystalline material. The mechanism for THP precipitation is not clear but is probably related to the mucosal changes, including inflammation and necrosis, which is always seen in areas of THP deposition. Follow-up study did not show any bladder abnormalities pertinent to THP deposition. In summary, THP is frequently seen in bladder tissue and most probably represents an incidental finding of morphologic interest but of no clinical significance.