Background: The predominant pattern of failure for Head and Neck Squamous Cell Carcinoma (HNSCC) is locoregional disease. Salvage surgery remains the standard of care for operable disease. Re-irradiation after previous full course radiotherapy generally has been considered contraindicated. Since anti-PD-1 antibodies were efficacious and safety in recurrent/metastatic HNSCC, this study aimed to evaluate the efficacy and safety of adjuvant toripalimab (anti-PD-1 antibody) in recurrent, previously irradiated HNSCC treated with salvage surgery. Methods: This study was a single-arm, phase II study. Patients with HNSCC occurring in an area of previously irradiated and with at least one high risk factors after salvage surgery (1- positive margin; 2- extranodal extension; 3- rStaging T3-4/N2-3/T2N1) were enrolled. In the Stage I of 12 patients, patients received toripalimab 240mg once every 3 weeks until confirmed disease progression or unacceptable toxicity, for 12 months. In the stage II of 8 patients with PD-L1 CPS≥1, patients received toripalimab combined with S-1, which was given orally at 25 mg/m², twice daily, on day 1 to 14, repeated every 21 days for 4-6 cycles. The primary endpoint was 1-year progression-free survival (PFS). We hypothesized a 1-year PFS of at least 56% and assumed a null hypothesis of 34%. A retrospective cohort of 16 patients was compared. Results: Between May 2019 and December 2020, 20 patients were enrolled. High-risk factors included ENE (35%), positive margin (25%), T3-4(30%) and T2N+(10%). Seventeen patients have PD-L1 CPS≥1 and 3 patients have CPS＜1. With a median follow-up of 11.2 months, estimated 1-year PFS and overall survival was 57.0% (95% confidence interval, 32%– 77%) and 79.2% (51%–91%). The primary PFS endpoint has exceeded the hypothesis and its median has not been reached. When compared to the retrospective cohort, the PFS was significantly better(p=0.001)，even for Stage I patients(Median PFS: 5.1 vs 3.7 months, p=0.03 ). Stage II patients resulted a better PFS and OS compare to stage I (p=0.02 and p=0.002). For patients with CPS≥1, 1-year PFS and OS was 79.1% (95% confidence interval, 51%–91%) and 91.7%(68%–99%), which were significantly better than patients with CPS＜1 (p=0.001 and p=0.05). Adjuvant Toripalimab or combine with S-1 was well-tolerated with no grade 3-4 toxicity and dose interruption as a result of treatment-related adverse event only occurred in 2 patients. Flow cytometry revealed that patients with short PFS had fewer baseline overall count of B cells(p=0.09). Conclusions: Adjuvant Toripalimab or combined with S-1 after salvage surgery is efficacious and safety in recurrent, previously irradiated HNSCC, and a better PFS was observed in patients treated with combined therapy and with CPS≥1. Further randomized trials are warranted. Clinical trial information: NCT04126460