Although several programmed cell death (PD)-1 inhibitors are approved for the first-line treatment of advanced urothelial carcinoma, their efficacy remains unknown in cisplatin-ineligible patients with upper tract urothelial carcinoma (UTUC) compared with gemcitabine plus carboplatin. Data for patients with UTUC were retrospectively retrieved from the electronic medical records of nine institutions between 2018 and 2021. Patients considered ineligible for cisplatin who received either PD-1 inhibitors (n = 70) or gemcitabine plus carboplatin (n = 53) were included. Efficacy was assessed using Response Evaluation Criteria in Solid Tumors. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The objective response rate (ORR) was comparable between the PD-1 inhibitor and carboplatin-gemcitabine groups (38.6% versus 41.5%). Median PFS was 5.0 months (95% confidence interval [CI]: 2.0-8.0) in the PD-1 inhibitor group, versus 7.0 months (95% CI: 5.8-8.2) in the carboplatin-gemcitabine group (hazard ratio [HR] = 0.741, 95% CI: 0.485-1.132, p = .166). Median OS was 18 months (95% CI: 4.1-31.9) in the PD-1 inhibitor group, compared with 14 months (95% CI: 12.1-15.9) in the carboplatin-gemcitabine group (HR = 0.731, 95% CI: 0.426-1.256, p = .257). The duration of response was significantly longer in the PD-1 inhibitor group than in the carboplatin-gemcitabine group (not reached vs. 9 months, p < .001). Treatment-related adverse events were less frequent in the PD-1 inhibitor group than in the carboplatin-gemcitabine group (57.1% vs. 77.3%). In conclusion, PD-1 inhibitors displayed promising efficacy with less toxicity and longer DOR in the first-line treatment of UTUC in patients ineligible for cisplatin-based chemotherapy.© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.