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Purpose Patients with very-high risk clear cell renal cell carcinoma (ccRCC) remain at substantial risk of recurrence after nephrectomy. However, heterogeneity in benefit from adjuvant immunotherapy observed in the KEYNOTE-564 trial, together with limited prospective data in this population, warrants further investigation.Methods This multicenter, prospective, non-randomized, controlled phase II trial enrolled patients with very-high risk ccRCC following nephrectomy. Patients received either adjuvant penpulimab or routine surveillance, with 1:1 propensity score matching (PSM) applied to balance baseline characteristics. The primary endpoint was disease-free survival (DFS), with secondary endpoints including overall survival (OS) and safety. Plasma proteomic and metabolomic profiling was conducted for exploratory analyses.Results Given the non-randomized design, baseline imbalances were addressed by PSM, yielding well-balanced cohorts of 87 patients per group. Adjuvant penpulimab was associated with improved DFS compared with surveillance (HR, 0.37; 95% CI 0.16 to 0.89; p=0.026), whereas OS data remained immature. Consistent with Kaplan-Meier estimates, 1-year (94.25% vs 80.46%) and 2-year (88.68% vs 75.38%) DFS rates favored the penpulimab group (log-rank p=0.026). Penpulimab was generally well tolerated, with most treatment-related adverse events being grade 1–2. Plasma proteomic and metabolomic analyses revealed enrichment of immune response-related pathways in patients without disease progression, with circulating biomarkers associated with DFS.Conclusions Adjuvant penpulimab was associated with improved DFS and a manageable safety profile in patients with very-high risk ccRCC. Plasma-based biomarkers associated with disease progression may inform postoperative risk stratification and warrant further validation.Trial registration number ChiCTR2200062189.