BACKGROUND: Interleukin (IL)-2 and interferon (IFN)-α are used as first-line treatment for patients with metastatic renal cell carcinoma (RCC), but response rates to these drugs are low. The multityrosine kinase inhibitor sunitinib malate targets the vascular endothelial growth factor receptor and platelet-derived growth factor receptor, both of which are activated in RCC through von Hippel-Lindau gene pathway secretion of their respective ligands VEGF and platelet-derived growth factor. Sunitinib has shown promise in patients with cytokine-resistant RCC treated in uncontrolled trials. OBJECTIVE: To compare sunitinib with IFN-α as first-line treatment for metastatic clear-cell RCC. DESIGN: Adult patients with metastatic RCC of clear-cell histology, previously untreated with systemic therapy, were enrolled between August 2004 and October 2005 in this international, randomized phase III trial. Patients were required to have measurable disease, good performance status, and adequate hematologic, renal, hepatic and cardiac function, and coagulation status. INTERVENTION: Patients were randomized in a 1:1 ratio to either first-line treatment with sunitinib (50 mg orally, once daily for 4 weeks, then 2 weeks without treatment, in 6-week cycles) or IFN-α (titrated to 9 MU subcutaneously 3 times a week). OUTCOME MEASURES: The primary outcome of the trial was progression-free survival (PFS), and secondary outcomes were overall survival, safety, objective response rate (according to RECIST), and patient-reported quality of life. RESULTS: In all, 750 patients were enrolled from centers in Australia, Canada, Brazil, Europe and the US. There was a higher frequency of adverse events of all grades in the sunitinib group than in the IFN-α group. Sunitinib caused diarrhea, emesis, neutropenia, leukopenia, thrombocytopenia, hypertension, and hand-foot syndrome more frequently than did IFN-α. Higher rates of lymphopenia, fatigue, pyrexia, myalgia, chills and influenza-like symptoms were seen in the IFN-α group than the sunitinib group. Median PFS was 5 months in the IFN-α group and 11 months in the sunitinib group (hazard ratio 0.42, 95% CI 0.32-0.54; P<0.001). Median PFS was longer in the sunitinib group than in the IFN-α group for all prognostic risk groups. Median overall survival had not been reached at the time of analysis, but there was a trend towards improved survival in the sunitinib group compared with the IFN-α group (hazard ratio for death 0.65, 95% CI 0.45-0.94; P = 0.02) and patients receiving sunitinib had a higher objective response than those receiving IFN-α (31% versus 6%; P<0.001). Health-related quality of life was better in the sunitinib group than the IFN-α group (P<0.001). CONCLUSION: Sunitinib targets the activity of angiogenic growth factors and produces favorable results in patients with metastatic clear-cell RCC. This trial demonstrated longer PFS and higher response rates for sunitinib treatment compared with IFN-α treatment in patients with metastatic RCC.