Background: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery has been the standard treatment option for locally advanced esophageal squamous cell cancer (ESCC). However, only 30% to 40% of patients can achieve pathologic complete response (pCR) after nCRT with favorable prognosis. To improve the efficacy of neoadjuvant therapy is an urgent clinical need. Immunotherapy has demonstrated promising results in advanced EC. Among patients received nCRT, PD-1 inhibitor has also provided a benefit as adjuvant treatment. However, the efficacy and safety of PD-1 inhibitor in neoadjuvant treatment still need to be confirmed. The aim of this study was to evaluate the efficacy and safety of the nCRT combined with perioperative toripalimab in locally advanced ESCC. Methods: A prospective, single-armed, exploratory trial was conducted and the key criteria included: resectable thoracic ESCC stage T1-4aN1-2M0 or T3-4aN0M0 according to the 8th edition of the AJCC staging system; aged 18̃75 years old; ECOG PS 0-1. All patients received radiation therapy scheme: 41.4Gy in 23 fractions over 5 weeks, concurrently with 5 cycles of paclitaxel/cisplatin (paclitaxel 45mg/m2 and cisplatin 25 mg/m2) on days 1, 8, 15, 22, 29 and 2 cycles of toripalimab 240 mg every 3 weeks after chemoradiotherapy for neoadjuvant therapy. Esophagectomy is performed 6-8 weeks after CRT completion and after operation patients received 4 cycles of toripalimab 240 mg every 3 weeks for adjuvant treatment. The primary endpoint was major pathological response (MPR: TRG1 and 2) rate. The secondary endpoints were survival outcomes (DFS and OS) and adverse events. Results: A total of 20 patients were enrolled from Jul 2020 to Jan 2022.13 patients have completed surgery in which 10 completed adjuvant immunotherapy, 3 patients have completed neoadjuvant therapy awaiting surgery, and 4 patients are still receiving neoadjuvant chemoradiotherapy. The overall pCR rate was 54% (7/13) and the pCR rate in primary tumor was 62% (8/13). Of the 13 patients, 10 (77%) had MPR (TRG 1 or 2). Treatment-related adverse effects (TRAEs) of any-grade occurred in 13 of 13 (100%) patients and those of grade 3-4 in 7 (54%). The most common any-grade TRAEs were lymphopenia (13/13, 100%), leukopenia (9/13, 69%), esophagitis (6/13, 46%), neutropenia (4/13, 31%) and nausea (3/13, 23%). The grade 3 TRAEs included lymphopenia (7/13, 54%), leukopenia (2/13, 15%), neutropenia (2/13, 15%) and anastomotic fistula (1/13, 8%). Most commonly immune-related adverse events (irAEs) were thyroid dysfunction (2/13, 15%) and pneumonia (1/13, 8%) and all were grade 1̃2. None of these 13 patients had any recurrence within a median follow-up of 6 months after operation. Conclusions: NCRT combined with perioperative toripalimab is feasible and safe for locally advanced resectable ESCC and seems to bring better tumor response. Long-term survival outcomes remain to be determined. Clinical trial information: NCT04437212.