Background: The randomized, multicenter, double-blind, phase 3 KEYNOTE-564 study (NCT03142334) showed that adjuvant pembrolizumab improved disease-free survival (DFS) compared with placebo following nephrectomy in participants (pts) with ccRCC at an increased risk of recurrence. We report results from the third prespecified interim analysis with a median follow-up of ~57 months. Methods: Pts were aged ≥18 years and had histologically confirmed ccRCC with or without sarcomatoid features, increased risk of recurrence, ECOG PS of 0 or 1, nephrectomy and/or metastasectomy ≤12 weeks before randomization, and no prior systemic therapy for RCC. Pts were randomly allocated 1:1 to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for ≥17 cycles (~1 year) or until disease recurrence, intolerable toxicity, or withdrawal of consent. DFS by investigator assessment was the primary end point. Overall survival (OS) was a key secondary end point. Safety was a secondary end point. Results: 994 pts were randomized 1:1 to pembrolizumab (n=496) or placebo (n=498). The median time from randomization to data cut-off date of September 15, 2023, was 57.2 months (range, 47.9−74.5). Statistically significant improvement in OS was observed with pembrolizumab vs placebo (medians not reached, HR 0.62, 95% CI 0.44−0.87; P=.0024). A total of 55 OS events were observed in the pembrolizumab arm and 86 in the placebo arm. The estimated OS rate at 48 months was 91.2% with pembrolizumab and 86.0% with placebo. OS benefit was observed across key subgroups, including in pts with M0 disease (HR 0.63, 95% CI 0.44−0.90) or M1 NED (HR 0.51, 95% CI 0.15−1.75), with PD-L1 CPS <1 (HR 0.65, 95% CI 0.31−1.38) or CPS ≥1 (HR 0.62, 95% CI 0.42−0.91), and with presence (HR 0.69, 95% CI 0.28−1.70) or absence (HR 0.57, 95% CI 0.39−0.84) of sarcomatoid features. The observed DFS benefit with pembrolizumab vs placebo was consistent with prior interim analyses (HR 0.72; 95% CI 0.59−0.87). No new safety signals were observed. Conclusions: After a median of ~57 months of follow-up, adjuvant pembrolizumab demonstrated a statistically significant and clinically meaningful improvement in overall survival versus placebo in participants with RCC at increased risk of recurrence post surgery. KEYNOTE-564 is the first phase 3 study to show improved survival with any adjuvant therapy in RCC. These results continue to support adjuvant pembrolizumab as a standard of care. Clinical trial information: NCT03142334.