Background: Surgery is standard treatment for nonmetastatic renal cell carcinoma (RCC). Unfortunately, patients (pts) with stage II or III RCC have high risk of relapse with 5-year disease-free survival rates of ~51%–56%; prevention of recurrence is an unmet need. In CheckMate 214, first-line nivolumab plus ipilimumab (NIVO+IPI) demonstrated significant overall survival improvements in pts with advanced/metastatic RCC, with a manageable safety profile. Moreover, while not yet confirmed in randomized controlled trials, evidence suggests that anti-PD-(L)1 monotherapy may provide sufficient clinical activity in some pts with advanced RCC. These findings indicate a potential for improved clinical outcomes in the early-stage adjuvant RCC setting. As such, the phase 3, double-blind CheckMate 914 study will evaluate NIVO and NIVO+IPI vs placebo in pts with high risk of relapse after nephrectomy (NCT03138512). Methods: Key inclusion criteria: radical or partial nephrectomy with negative surgical margins > 4 weeks and ≤12 weeks before randomization; predominantly clear cell histology; pathologic TNM staging T2a (grade [G] 3 or 4), T2b (any G), T3 (any G), or T4 (any G) N0M0, or any T (any G) N1M0; Eastern Cooperative Oncology Group performance status ≤1; no clinical/radiological evidence of macroscopic residual disease or distant metastases post-nephrectomy; and tumor tissue obtained ≤3 months pre-enrollment. Key exclusion criteria: conditions requiring corticosteroid or immunosuppressive systemic treatment, autoimmune disease, prior treatment with drugs specifically targeting T-cell co-stimulation or checkpoint pathways, and prior systemic treatment for RCC. In part A, pts are randomized 1:1 to receive NIVO+IPI or placebo infusions; in part B, pts are randomized 1:1:2 to receive NIVO+IPI, placebo infusions, or NIVO with IPI placebo. All treatments are given for 24 weeks or until disease recurrence, unacceptable toxicity, or withdrawal of consent. Stratification factors: TNM staging and type of nephrectomy procedure. Primary endpoint: disease-free survival per blinded independent central review (part A: NIVO+IPI vs placebo; part B: NIVO vs placebo). Secondary endpoints: overall survival (part A: NIVO+IPI vs placebo; part B: NIVO vs placebo and NIVO+IPI vs NIVO), disease-free survival (part B: NIVO+IPI vs NIVO), and safety. Enrollment in the study is ongoing. Total target enrollment across parts A and B is 1600 pts. Clinical trial information: NCT03138512.