Background: The typical management for renal cell carcinoma (RCC) is nephrectomy. Despite this, patients with intermediate- to high-risk advanced disease can experience relapse with metastatic, usually incurable, disease. Adjuvant therapies are needed for patients at risk for recurrence after nephrectomy. Upregulation of the programmed death 1 (PD-1) pathway is associated with poor prognosis in RCC, and drugs to target the PD-1 pathway have shown efficacy and reasonable safety in metastatic RCC. Therefore, the PD-1 pathway may represent a novel target to prevent disease recurrence. The randomized, double-blind, placebo-controlled phase 3 KEYNOTE-564 trial (NCT03142334) is designed to evaluate the efficacy and safety of pembrolizumab in the adjuvant treatment of RCC after nephrectomy. Methods: Key inclusion criteria include age ≥18 years, histologically confirmed clear cell RCC of intermediate-high risk (pT2, grade 4 or sarcomatoid, N0 M0; or pT3, any grade, N0 M0), high risk (pT4, any grade, N0 M0; or pT any stage, any grade, N+ M0), or M1 NED; no prior systemic therapy for advanced RCC; negative surgical margins; Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; and tumor sample available for biomarker analyses. Patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg or placebo every 3 weeks by intravenous infusion. Treatment will continue until disease recurrence, treatment discontinuation, or the completion of 17 cycles. Imaging will be performed every 12 weeks. The primary end point is disease-free survival (DFS) per investigator assessment. The secondary end point is overall survival (OS). Additional secondary analyses include safety and tolerability, pharmacokinetic parameters, antidrug antibodies, and DFS and OS per PD-L1 expression status. Biomarkers that may be associated with response will be evaluated as an exploratory objective. Recruitment will continue until ~950 patients are enrolled. Clinical trial information: NCT03142334