Background: Approximately 50% of primary metastatic nasopharyngeal carcinoma (mNPC) patients who received sequential chemoradiotherapy experience disease progression within one year. Improvements in therapy are greatly needed. This phase II study aimed to investigate the efficacy and safety of programmed cell death protein-1 (PD-1) inhibitor combined with sequential chemoradiotherapy in de novo mNPC. Methods: Patients who demonstrated complete or partial response following 3 cycles of cisplatin and fluorouracil (PF) were enrolled. Eligible patients received 3 more cycles of PF and subsequent radiotherapy plus toripalimab every three weeks at a fixed dose of 240 mg. The primary end point was objective response rate (ORR) at three months after radiotherapy, and the secondary end points were progression-free survival (PFS), disease control rate (DCR) and safety profiles. Exploratory study included biomarker analysis and efficacy comparation based on a historical cohort. A Simon’s two-stage optimal design with one-sided type I error rate of 5% and power of 80% was utilized to compare a null hypothesis ORR of 54% against an alternative of 80%. Target accrual was a minimum of 22 patients (stage 1 and 2 combined). Results: Of the 22 enrolled patients (7 women and 15 men; median age of 54.5 years [IQR 40.5-57.5 years]), the ORR at three months after radiotherapy was 81.8% (22.7% complete response, n = 5; 59.1% partial response, n = 13), and the DCR was 81.8%. The median PFS was 19.4 months (95% CI 10.8-NR). Grade 3-4 adverse events occurred in 15 (68.2%) patients; two patients (9.1%) had grade 2 or 3 immune-related adverse events and discontinued toripalimab. This trial met its primary objective of demonstrating a significant ORR versus historical controls (81.8% vs. 54%, P = 0.024). Elevation of plasma EBV DNA post radiation was associated with worse median PFS (10.5 vs. 19.4 months; hazard ratio = 4.23, 95% CI 1.0-17.9; P = 0.033). Conclusions: The addition of toripalimab to sequential chemoradiotherapy displayed promising tumor response and manageable safety profile in primary mNPC. These results support a potential role of PD-1 inhibition as consolidation therapy in the first-line treatment of primary mNPC. Clinical trial information: NCT04398056.