Background: Two randomized trials in the cytokine era clearly showed that cytoreductive nephrectomy (CN) increased life expectancy in metastatic renal cell carcinoma (mRCC) patients (pts). The survival benefit of first-line sunitinib and pazopanib has been demonstrated, but the majority of pts enrolled in the pivotal phase III studies had undergone CN. Therefore it is unclear if similar survival benefit could be achieved without CN with these new targeted agents. Methods: A total of 270 mRCC pts will be randomized to receive CN followed by TKIs vs upfront TKIs. Patients will receive pazopanib 800 mg orally daily or sunitinib 50 mg daily, 4 weeks on/ 2 weeks off. The choice of TKI will be done according to investigator’s clinical practice. Primary objective: To compare clinical benefit, as measured by overall survival (OS), provided by CN followed by TKIs vs upfront TKIs in pts with mRCC. Secondary objectives: To compare clinical benefit, as measured by progression-free survival (PFS) and response rate (RR) provided by CN followed by TKIs vs upfront TKIs, Safety. Exploratory study: Evaluation of predictive role of CTCs count and ctDNA at baseline, before and after surgery (in pts undergoing CN), 24 weeks after randomization and at the time of disease progression Key inclusion criteria: Favorable or intermediate MSKCC or Heng prognostic risk group; diagnosis of RCC with a clear-cell component; resectable asymptomatic mRCC with primary in tumor in place; up to 3 different metastatic sites; ≥ 3 metastatic lesions. Key exclusion criteria: Widespread disease ( > or = 4 metastatic organ sites) Oligometastatic disease suitable of metastasectomy ( < 3 lesions confined at one organ site) Statistical plan: The sample size was calculated in order to compare 5-year OS between subjects randomized to receive CN followed by TKIs and those randomized to receive upfront TKIs. A total of 191 deaths will yield 80% power to detect a hazard ratio of 1.5 of upfront TKIs vs CN followed by TKIs with an overall type 1 error of 0.05 (two-sided log-rank test). Such a HR corresponds to an increase in the 5-year OS, from an anticipated value of 10% for TKIs to 21.5% for CN followed by TKIs. Clinical trial information: NCT02535351