<b><i>Introduction:</i></b> The aim of this study was to test for differences in overall (OS) and progression-free survival (PFS) rates and toxicity in first-line immune checkpoint inhibition (IO) combination therapy in metastatic renal-cell carcinoma (mRCC) patients. <b><i>Methods:</i></b> Between November 2017 and April 2021, 104 patients with histologically confirmed mRCC from 6 tertiary referral centers with either IO + IO (nivolumab + ipilimumab, <i>n</i> = 68) or IO + tyrosine kinase inhibitor (TKI) (pembrolizumab + axitinib, <i>n</i> = 36) were included. Kaplan-Meier and Cox regression analyses tested for OS and PFS differences. <b><i>Results:</i></b> Of 104 mRCC patients, 68 received IO + IO (65.4%) and 36 IO + TKI (34.6%) therapy, respectively. Median age was 67 years (interquartile range: 57–70.3). Patients receiving IO + TKI were less likely to be poor risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium score (16.7 vs. 30.9%) and presented with lower T-stage, compared to IO + IO treated patients. Median PFS was 9.8 months (CI: 5.3–17.6) versus 12.3 months (CI: 7.7 – not reached) for IO + IO versus IO + TKI treatment, respectively (<i>p</i> = 0.22). Median OS was not reached, survival rates at 12 months being 73.9 versus 90.0% for IO + IO versus IO + TKI patients (<i>p</i> = 0.089). In subgroup analyses of elderly patients (≥70 years, <i>n</i> = 38), IO + TKI treatment resulted in better OS rates at 12 months compared to IO + IO (91.0 vs. 57.0%; <i>p</i> = 0.042). <b><i>Conclusion:</i></b> IO + IO and IO + TKI as first-line therapies in mRCC patients were both comparable as for the oncological outcome and toxicity.