OBJECTIVE We examined whether cimetidine could augment the efficacy of interferon-alpha therapy for advanced renal cell carcinoma. METHODS Of 31 male and 6 female patients treated with interferon-alpha and cimetidine 21 had metastases at diagnosis and 15 had a recurrence after nephrectomy. One patient had a primary tumor with thrombus in the inferior vena cava. Lymphoblastoid interferon-alpha was administered at 5 megaunits daily intramuscularly 5 to 7 days a week for at least 8 weeks, and cimetidine was administered orally at 800 mg. daily in 4 divided doses. The evaluable tumors included 30 in the lung, 6 lymph nodes, 5 bone, 4 kidney and 1 inferior vena cava. RESULTS Combined therapy with interferon-alpha and cimetidine resulted in a complete response in 7 patients, a partial response in 8, stable disease in 12 and progression in 10. The objective response rate was 41%. The lung metastasis showed the best response to combined therapy. The 5-year survival rates for patients with and without response, and overall were 74, 20 and 41%, respectively. Histopathologically, high grade tumors had a better response to combined therapy than did low grade tumors. CONCLUSIONS Combined therapy with interferon-alpha and cimetidine for advanced renal cell carcinoma resulted in a definitively good response. A prospective randomized trial should be performed to elucidate the efficacy of the combined therapy.