Aim: To evaluate the efficacy of immune checkpoint inhibitors (ICIs) plus tyrosine kinase inhibitors (TKIs) as second-line treatment in patients with metastatic renal cell carcinoma (mRCC). Patients & methods: Baseline and follow-up data from patients with mRCC treated with second-line ICIs plus TKIs or TKIs alone from a single institution were retrospectively gathered. Results: A total of 110 patients were included. The objective response rate was higher among patients treated with ICIs plus TKIs than those treated with TKIs alone (36.5 vs 12.1%; p = 0.002). Treatment with ICIs plus TKIs was associated with longer progression-free survival (15.0 vs 9.0 months; p = 0.009) and overall survival (not reached vs 16.0 months; p = 0.018) than TKI monotherapy. The survival rates at 2 (83.0 vs 74.4%; p = 0.426) and 3 years (58.1 vs 47.5%; p = 0.214) between the two groups were not statistically different. Notably, patients with certain clinicopathological features tended to gain more survival benefits with combined therapy. Conclusion: ICIs plus TKIs showed superior progression-free survival time and tumor response rate over TKIs alone as second-line treatment in patients with mRCC. Future randomized prospective trials are necessary to validate these preliminary findings.