Background: Anti-programed cell death-1 (PD-1) monotherapy is a part of the standard therapy for cutaneous melanoma but has demonstrated low efficacy in mucosal melanoma. This study evaluated the efficacy and safety of atezolizumab plus bevacizumab as a first-line therapy in patients with advanced mucosal melanoma. Methods: This multicenter, open-label, single-arm, phase 2 study utilized a Simon’s two-stage design. Atezolizumab (fixed-dose, 1200 mg) and bevacizumab (7.5 mg/kg) were administered by intravenous infusion every 3 weeks. The primary endpoint was objective response rate (ORR), determined by the investigator per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), disease control rate (DCR), and safety with adverse events summarized using NCI-CTCAE v5.0. Results: In total, 43 patients were enrolled, including 20 (46.5%) with unresectable and 23 (53.5%) with metastatic mucosal melanoma. Median follow-up was 13.4 months at data cut-off (July 30, 2021). Forty patients were evaluable for response: In stage I analysis set (n=22), the best confirmed ORR according to RECIST v1.1 was 40.9% (9/22; 95% CI 20.7-63.7), including one CR and eight PRs. The ORR in the FAS population was 45.0% (95% CI, 29.3-61.5) (1 CR, 17 PRs) and the DCR was 65.0% (95% CI, 48.3-79.4). The median PFS was 8.2 months (95% CI, 2.7-9.6), the 6- and 12-month PFS rates were 53.4% (95% CI, 36.6-67.6) and 28.1% (95% CI, 14.2-43.9), respectively. The median OS was not reached (NR) (95% CI, 14.4-NR). The 6- and 12-month OS rates were 92.5% (95% CI, 78.5-97.5) and 76.0% (95% CI, 57.1-87.5), respectively. The median DOR was 12.5 months (95% CI, 5.5-NR). Overall, 90.7% (39/43) of patients experienced treatment-related adverse events, and 25.6% (11/43) experienced grade ≥ 3 events. Conclusions: Atezolizumab in combination with bevacizumab showed promising efficacy and a manageable safety profile in patients with advanced mucosal melanoma. Research Sponsor: Shanghai Roche Pharmaceuticals Ltd., China. Clinical trial information: NCT04091217.