Background: Ipi + Nivo or ICI + TKI are the 1L approved treatments for I/P risk mccRCC. In their respective registration trials, they were all compared to single-agent TKI. The comparative effectiveness of Ipi + Nivo vs. ICI + TKI has not been reported. Herein, we use a large real-world database to compare survival outcomes of pts receiving 1L Ipi + Nivo vs. ICI + TKI. Methods: This IRB approved retrospective study used the nationwide Flatiron Health electronic health record database. The de-identified data originated from approximately 280 cancer clinics (~800 sites of care). Inclusion: (1) pts with metastatic RCC with clear cell histology (2) I/P risk disease per IMDC criteria (3) Receipt of 1L treatment (Rx) with Ipi + Nivo or ICI + TKI (i.e. axitinib + pembrolizumab, cabozantinib + nivolumab, lenvatinib + pembrolizumab or axitinib + avelumab) between 11-08-2016 to 1-27-2023. Pts were classified into two groups based on Rx with Ipi + Nivo or ICI + TKI. Endpoints: Real-world overall survival (rwOS) and real-world time to next therapy (rwTTNT), summarized via Kaplan-Meier survival estimates with 95% confidence interval (CI) and compared in the context of propensity score (PS) matching weighted analysis and Cox proportional hazard model (PSM- CoxHzM). PS model included baseline covariates: age, race, smoking status, practice type, insurance, year of 1L, IMDC risk factors (all six), and missingness of covariates. All analysis done using R version 4.2.3. Results: Of 12,285 pts with mRCC in the dataset, 1033 met eligibility and were included (564 pts: Ipi + Nivo and 469 pts: ICI + TKI). The median rwOS for Ipi + Nivo was 30 months (mo) [95% CI 26 – 35] vs. 34 mo [95% CI 28 – 41] for ICI + TKI (HR 1.02, 95% CI 0.84 – 1.24, p = 0.81). The median rwTTNT was 9.1 mo [95% CI 8 – 11] for Ipi + Nivo vs. 15 mo [95% CI 14 – 18] for ICI + TKI (HR 1.29, 95% CI 1.09 – 1.51, p = 0.002). After PS matching, no significant difference in rwOS was noted between both groups (HR 1.01, 95% CI 0.83 – 1.24, p = 0.89). However, rwTTNT was significantly shorter with Ipi + Nivo compared to the ICI + TKI (HR 1.24, 95% CI 1.05 – 1.47, p = 0.011). Conclusions: In this study rwOS was comparable between pts receiving Ipi + Nivo vs. ICI + TKI Rx while rwTTNT was better with ICI + TKI. These data can help clinicians in pts counseling, and treatment selection. In the absence of validated biomarkers, the choice of 1L Rx for pts mccRCC should primarily depend on clinical factors (performance status, comorbidities, pt compliance and preference), Rx characteristics (toxicity profile) and disease status (urgency of response).