Fifty patients with locally advanced or metastatic renal cell carcinoma were treated with coumarin (1,2-benzopyrone) at 100 mg orally daily starting on day 1 and cimetidine 300 mg orally four times a day starting on day 15. When disease progressed, coumarin was escalated to 100 mg orally four times a day. Three patients (6%; 95% confidence interval [CI], 2% to 17%) achieved a partial response, one of those after dose escalation. In addition, one patient had a minor response, then progressing disease, and again had a minor response after dose escalation. All four responders had nonassessable primary tumors (three had had prior nephrectomy and one a renal angioinfarction). The only major toxicity was renal (37 patients had minor to moderate elevations in serum creatinine level). Immunologic studies (hypersensitivity skin testing, lymphocyte blastogenesis response, number of lymphocytes, T lymphocytes, T helper and T suppressor subsets, and T helper:suppressor ratio), performed before and after therapy, showed a relative lymphopenia and decreased hypersensitivity skin-testing results at baseline, and a general decline over time in the number of T cells and T helper and T suppressor subsets. There was no enhancement in any of the immunologic parameters tested. The response rate was 6%, lower than previously reported; a general immunodeficiency was noted at baseline, and the lymphopenia worsened with progressing disease, unaffected by therapy.