Background <p>Immune checkpoint inhibitor (ICI)-based regimens are the standard first-line therapy for advanced renal cell carcinoma (RCC). However, their comparative effectiveness and safety in routine clinical practice remain incompletely characterised.</p> Objective <p>The aim of this study was to systematically synthesise comparative real-world evidence on the efficacy and safety of ICI-based regimens in patients with advanced RCC.</p> Methods <p>A systematic search of MEDLINE, Embase, and Scopus was conducted from database inception to 21 January 2026, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Observational cohort studies evaluating ICI-based regimens in advanced RCC with an active comparator were included. Primary efficacy outcomes were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Safety outcomes included treatment-related adverse events. Study quality was assessed using the Newcastle–Ottawa Scale, with efficacy and safety evaluated separately. Owing to substantial clinical and methodological heterogeneity, findings were synthesised narratively.</p> Results <p>Overall, 58 retrospective cohort studies comprising 35,215 patients were included. Most studies evaluated first-line therapy and involved populations with mixed histology and heterogeneous prognostic risk profiles. Overall, ICI-tyrosine kinase inhibitor (TKI) combinations were generally associated with more favourable survival outcomes compared with dual ICI therapy or TKI monotherapy, with the most consistent benefit observed for PFS. Evidence comparing dual ICI therapy with TKI monotherapy was mixed, with most studies reporting no statistically significant differences in survival outcomes. Comparative safety data were limited, with the majority of studies relying on unadjusted descriptive analyses, limiting robust comparative interpretation of safety outcomes.</p> Conclusions <p>Real-world evidence suggests that ICI–TKI combinations are associated with more favourable survival outcomes compared with other treatment options in advanced RCC, while the comparative effectiveness of dual ICI therapy versus TKI monotherapy remains inconclusive. Substantial heterogeneity and methodological limitations, particularly in safety reporting, limit definitive interpretation. High-quality real-world studies incorporating robust confounding adjustment and clinically relevant subgroup analyses are needed to better inform treatment selection in routine practice.</p> Trial Registry <p>International Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD420251149614.</p>