BACKGROUND: Novel combination therapies have been shown to improve the outcomes of treatment-naive patients with locally advanced or metastatic renal cell carcinoma (aRCC). However, the optimal systemic therapy for aRCC of favorable risk has yet to be clarified. We aimed to evaluate the efficacy and safety of different immunotherapy (IO) combinations, either with another IO (IO-IO) or with an antiangiogenic (IO-TKI), versus sunitinib in the first-line setting in aRCC patients with favorable IMDC risk. METHODS: We conducted a systematic search for evidence in PubMed, Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials published up to February 2021. The GRADE approach was used to assess the quality of evidence. Survival hazard ratios were extracted for analysis in the favorable-risk aRCC subgroup (IMDC). A sensitivity analysis was performed excluding trials of combination therapy without TKI. RESULTS: Five randomized controlled phase III trials with a total of 1088 patients were included in the analysis. The studies compared different combinations versus sunitinib monotherapy. All clinical trials reported overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) data. Four out of five trials reported complete response (CR). There was no difference in OS nor PFS between treatment arms in the IMDC favorable-risk subgroup analysis (OS: HR = 1.07, 95% CI = 0.81-1.41; PFS: HR = 0.74, 95% CI = 0.46-1.19). A benefit in ORR and CR was found for combination therapy vs. sunitinib (ORR: HR = 1.89, 95% CI = 1.29-2.76; CR: HR = 3.58, 95% CI = 2.04-6.28). In the sensitivity analysis, including only IO-TKI vs. sunitinib, no difference in OS was found; however, an advantage in PFS was observed (OS: HR = 0.99, 95% CI 0.69-1.43; PFS: HR = 0.60 (0.45-0.81). The safety profile reported is consistent with previous reports. We did not find differences in the incidence of any adverse event (AE) or of grade ≥3 AEs. CONCLUSION: This meta-analysis shows that combinations of IO-KI as first-line treatment in favorable-IMDC-risk aRCC improve PFS, ORR, and CR, but not OS, versus sunitinib.