Background: A phase IB trial had showen promising antitumor activity with toripalimab (T, a PD-1 antibody) plus axitinib (A, a VEGF receptor inhibitor) in treatment-naive unresectable or metastatic mucosal melanoma. Now we conducted a phase II trial to compare the combined treatment with monotherapy. Methods: In this randomized, controlled, phase II trial, patients with pathologically confirmed treatment-naive unresectable or metastatic mucosal melanoma were stratified by PD-L1 expression and randomized 1:1:1 into three groups to receive treatment of T+A (toripalimab 240 mg i.v. every 3 weeks, axitinib 5 mg orally twice a day), T (toripalimab 240 mg i.v. every 3 weeks) or A (axitinib 5 mg orally twice a day). Subjects in T or A who meet the criteria after disease progression may cross over to receive T+A. The primary endpoint was progression-free survival (PFS). Secondary endpoints included Objective response rate (ORR), Duration of response (DOR), overall survival (OS), and safety. The protocol was registered at ClinicalTrials.gov (NCT03941795). This is the interim analysis for efficacy and safety. Results: Between Nov 2019 and Jan 2022, 51 patients were randomized (18 to T+A, 20 to T, and 13 to A due to preliminary efficacy analysis). Anatomic site of head and neck, gastrointestinal, gynecological were 49.0%, 29.4%, 21.6%, respectively. Stage II or III unresectable, M1a, M1b, M1c were 3.9%, 23.5%, 17.6%, 51.0%, respectively. PD-L1 positivity was defined as ≥1% of tumor cells and/or infiltrating immune cells and were identified in 55.6%, 45.0%, 53.8% patients in T+A, T, A group, respectively. 17, 17 and 12 patients could be evaluated in T+A, T and A group, respectively. 24 patients from T or A crossover to T+A group. At a median follow-up of 6.60 months, patients receiving T+A had a higher median PFS (5.83 vs 2.80 vs 1.40 months; HR = 0.538; 95% CI, 0.237 to 1.221; HR = 0.444; 95% CI, 0.182 to 1.081; P = 0.170), ORR (35.3% (29.7% if including crossover patients ) vs 17.6% vs 8.3%), DOR (82.4% (70.3% if including crossover patients) vs 52.9% vs 58.3%) versus T or A group. The median OS was not reached. 80.4% patients experienced treatment-related adverse events (TRAEs). The most common TRAEs were mild (grade 1 or 2) and included diarrhea, proteinuria, hand and foot syndrome, fatigue, elevated transaminase, elevated bilirubin, hypertension, hypo- or hyperthyroidism, and rash. Grade 3 or greater TRAEs occurred in 33.3%, 30.0%, 30.8% of patients in T+A, T, A groups. Conclusions: Toripalimab plus axitinib showed promising antitumor activity versus toripalimab or axitinib alone in patients with treatment-naive unresectable or metastatic mucosal melanoma. Clinical trial information: NCT03941795.