Treatment options for patients with metastatic renal cell carcinoma are limited. Interferon-alpha has an overall response rate of 10-15% in phase II and III clinical trials and is considered a standard option for patients. Though the anti-estrogen toremifene has shown only modest single agent activity in renal cell carcinoma, evidence for synergy of anti-estrogens with interferon-alpha exists in renal cell and other cancers. Therefore, a phase II trial was undertaken to test the combination of interferon-alpha and toremifene in advanced renal cell carcinoma. Thirteen patients with measurable metastatic or unresectable local disease were treated with interferon-alpha at a dose of 5 million units/m2 three times a week and daily oral toremifene at 300 mg daily in divided doses. Patients were treated for 12 weeks and then restaged. Clinical response was the primary endpoint of the trial. Four patients (31%) had evidence of stable disease at 12 weeks, while the remaining nine patients (69%) progressed on treatment. Toxicity was moderate, with grade 2 or 3 fatigue, nausea and anorexia each noted in 31% of patients. We conclude that the combination of interferon-alpha plus toremifene demonstrates no significant activity in advanced renal cell carcinoma.