We investigated the expression of cell-associated CAIX protein in histological sections of the transitional cell carcinoma (TCC) of the urinary tract and of the soluble form of CAIX (s-CAIX) shed by the tumor into the serum and urine of TCC patients. A total of 23 patients with histologically confirmed TCC or squamous cell carcinoma (SCC) were enrolled in the pilot study. Sixteen healthy individuals served as controls. Membrane-bound CAIX was present in the tumor cells near the endoluminal surface. Necrosis was observed in only 4 samples. Using Western blots, s-CAIX concentrated from urine was visualized as a double band at 50 and 54 kDa. In most cases, the presence of s-CAIX in the urine correlated with CAIX expression in the tumor. On the other hand, s-CAIX did not exceed the normal level in the serum of TCC patients. Urine from patients with TCC of the urinary bladder and renal pelvis contained s-CAIX, allowing the detection of tumors in approximately 70% of the patients. Moreover, two additional patients with suspected, but unconfirmed bladder tumor, with s-CAIX detected in urine, developed tumors identified as TCC within six months. We suggest that after a simple, rapid and sensitive test, monitoring s-CAIX levels in urine will be developed, it may be useful for early detection of relapse in patients following transurethral tumor resection.