Background: First-line treatment for mRCC includes I/N and A/P. These two regimens have not been compared in a randomized clinical trial as both CM-214 and KN-426 used single-agent tyrosine kinase inhibitors (TKIs) as the comparator. Meta-analyses suggest improved efficacy outcomes with A/P, but increased likelihood of complete response with I/N. We compared these treatments in the real-world. Methods: Data of consented mRCC patients with clear cell histology from the Canadian Kidney Cancer information system (CKCis) was obtained from January 2013 to December 2021. Treatment outcomes adjusting for age including overall survival (OS), progression free survival (PFS), and response rate (RR) for all patients and intermediate-poor risk patients were completed. Chi-square tests compared the frequency of side effects. Results: Among 547 patients, 360 received I/N and 187 received A/P. Median follow-up was 30.0 (0.1-112.1) months. Median duration of treatment was 6.9 (0.0-68.4) months for I/N and 20.2 (0.1-72.4) months for A/P. Intermediate-poor risk patients were higher in the I/N compared to A/P cohort (91.9% vs. 66.2%; p<0.0001). Cox regression for OS showed no difference between I/N compared to A/P (aHR 1.1, 95% CI [0.77-1.58], p=0.61). PFS showed no statistical difference but a trend for worse with I/N at 12.1 months compared to 22.3 months for A/P (aHR=1.2, 95% CI [0.95-1.62], p=0.11). RR was 40.9% with I/N compared to 56.0% in A/P (aOR 0.52, 95%CI [0.33-0.83], p=0.005). Subgroup analyses for the intermediate-poor risk mRCC patients showed no differences in OS (aHR 0.95, 95%CI [0.65-1.38], p=0.79) and PFS (aHR 1.21, 95%CI [0.90-1.62], p=0.21) between treatment groups but improved RR (aOR 0.58, 95%CI [0.35-0.96], p=0.06) with A/P. 61.7% of I/N patients compared to 79.1% of A/P suffered adverse events that led to a dose or schedule change (p<0.001). Most common toxicities for both groups include diarrhea, fatigue, transaminitis, rash, and anorexia. Conclusions: There was no difference in OS between mRCC patients treated with I/N compared to A/P. A/P demonstrates improved RR and a trend towards longer PFS at the expense of increased frequency of side effects. Despite a median follow-up of 30 months, the data is limited by a high amount of censoring.