Background: The anti-PD-1 antibody nivolumab (nivo) improves overall survival (OS) in metastatic treatment refractory RCC and is generally tolerable. In 2017, there is no standard adjuvant therapy proven to increase OS over surgery alone in non-metastatic (M0) disease. Mouse solid tumor models have revealed an OS benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivo in RCC patients (pts) have shown preliminary feasibility and safety with no surgical delays or complications. The PROSPER RCC trial will examine if the addition of perioperative nivo to radical or partial nephrectomy can improve clinical outcomes in pts with locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in M0 RCC, we propose a three-pronged, multidisciplinary approach of presurgical priming with nivo followed by resection and adjuvant PD-1 blockade. Methods: Tumorbiopsy prior to randomization is mandatory to ensure the correct diagnosis and will permit unparalleled correlative science in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. 766 pts with clinical stage ≥T2 or any node positive M0 RCC of any histology will be enrolled. The study arm will receive nivo 240mg IV for 2 doses prior to surgery followed by nivo adjuvantly for 9 months (q2 wks x 3 mo followed by q4 wks x 6 mo). The control arm will undergo the current standard of care: surgical resection followed by observation. Pts are stratified by clinical T stage, node positivity, and histology. There is 84.2% power to detect a 14.4% absolute increase in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 yrs (HR 0.70). The study is also powered to detect a significant OS benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the significance of the baseline immune milieu and changes after neoadjuvant priming and to identify predictive gene expression patterns. Additional collaborations are welcomed.