We assessed the role of cytoreductive surgery in patients with metastatic renal cell carcinoma (RCC) selected for interleukin-2 (IL-2)-based immunotherapy. Sixty-three consecutive newly diagnosed patients with metastatic RCC were treated at our institution between April, 1990 and October, 1994. The patients were selected based on their ability to undergo a radical nephrectomy and to receive a combination of interleukin-2 and interferon alfa (IFN-alpha). The mean age was 58.7 years (range, 34-74 years). All but one patient had an Eastern Cooperative Oncology Group performance status of 0 or 1, and presented with metastatic disease and locally advanced primary tumors. All patients successfully underwent cytoreductive nephrectomy, but 6 patients (10%) required concomitant resection of caval thrombus, 3 (5%) required partial hepatectomy, 2 (3%) needed duodenal repairs, and 1 (2%) required a splenectomy. Postoperative complications were observed in 8 patients (12.7%). There were no postoperative mortalities. Seven patients (11%) could not undergo immunotherapy because of myocardial infarctions (n = 2), no growth of tumor infiltrating lymphocytes (TILs) (n = 1), deterioration of performance status (n = 1), transient ischemic attack (n = 1), chronic renal failure (n = 1), and a diagnosis other than RCC (n = 1). Overall, 56 of 63 (88%) patients selected underwent immunotherapy. Among these 56 patients, a response rate of 33.9% [7 (12.5%) complete, and 12 (21.4%) partial] was observed. Moreover, the 2- and 3-year survival rates were 43% and 38%, respectively. Our results support the argument for an aggressive approach (surgery combined with IL-2-based immunotherapy including TILs) in the management of metastatic RCC. Further studies are needed to elucidate the individual contributions of these therapeutic processes.