We assayed sera from 24 patients with metastatic renal cell carcinoma for class specific antibody against urinary Tamm-Horsfall protein (THP) using indirect solid-phase radioimmunoassay techniques. Overall, 16 patients had elevated antibody levels (greater than 2 SD above the mean levels of control subjects). IgG against THP was elevated in eight of the patients, IgA in 12, and IgM in five. However, THP was not identifiable by immunohistochemical techniques in the sections of 15 of 24 tumors available for study. Nine of the 15 tumors were from patients with elevated antibody levels. Serum antibody against THP in patients with renal cell carcinoma appears to result from antigenic stimulation by THP derived from the urine rather than from the neoplasm.