Purpose We assessed the efficacy of the oral multitargeted tyrosine kinase inhibitor sunitinib in patients with metastatic clear cell renal cell carcinoma. Materials and Methods Patients with metastatic clear cell renal cell carcinoma were enrolled in this multicenter, phase II clinical trial. Major eligibility requirements were clear cell renal cell carcinoma histology, prior nephrectomy, measurable metastases and failed prior cytokine therapy as a result of disease progression. Sunitinib was given orally as second line therapy in 6-week cycles of 50 mg daily for 4 weeks, followed by 2 weeks off drug per treatment cycle. Response to sunitinib was rigorously assessed by an independent third party core imaging laboratory (central review). Results Of 106 patients enrolled in the study 105 were evaluated for response. As determined by independent third party assessment, the objective response rate was 33% (95% CI 24%–43%) with a median response duration of 14.0 months. Median time to progression and median progression-free survival in the 105 evaluable patients was 10.7 and 8.8 months, respectively. Median survival was 23.9 months and 43 patients remained alive at a median followup of 29.7 months. Conclusions The results of this trial demonstrate the efficacy of sunitinib for metastatic renal cell carcinoma. The optimal integration of surgery and sunitinib treatment requires further prospective investigation.