Background: No previous study has compared the efficacy and safety of first-line axitinib and sunitinib. We aimed to compare oncological outcomes and safety of axitinib and sunitinib in patients with treatment-naïve metastatic renal cell carcinoma (mRCC). Methods: We retrospectively evaluated 169 patients with mRCC who were treated with axitinib or sunitinib as the first-line therapy in five hospitals between October 2008 and August 2018.Oncological outcomes and safety were compared between axitinib (n = 68) and sunitinib (n = 101) groups. Inverse probability of treatment weighted (IPTW)-adjusted Cox regression analysis was performed to evaluate effects of first-line therapies on progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Results: Patients in the axitinib group were significantly older (66 vs 72 years) than those in the sunitinib group. Median relative dose intensity was significantly higher in the axitinib group (94 ± 62%) than in the sunitinib group (65 ± 20%; P = 0.001). Objective response rate was significantly higher in the axitinib group (21%) than in the sunitinib group (10%; P = 0.042). IPTW-adjusted Cox regression analysis revealed significant differences in CSS and OS but not in PFS between the two groups. Safety in terms of grade ≥3 adverse events was significantly different between the axitinib (34%) and sunitinib (55%) groups (P = 0.006). Conclusions: Compared with sunitinib, axitinib significantly prolonged CSS and OS and showed a safer profile as the first-line therapy for treatment-naïve mRCC.