Background: Definitive chemoradiotherapy (CRT) is the standard treatment option for unresectable locally advanced esophageal cancer. However, the loco-regional and distant recurrences after definitive CRT were as high as 50%. Immunotherapy targeting the PD-1/PD-L1 axis has demonstrated antitumor activity in advanced esophageal cancer. With the potential benefit of combining PD-1 blockade to CRT, we performed a phase II trial to evaluate the efficacy and safety of the combination of toripalimab (an anti-PD-1 antibody) and definitive CRT in locally advanced esophageal squamous cell carcinoma (ESCC). Methods: Patients with previously untreated, unresectable, stage II–IVA ESCC were enrolled. Patients received concurrent radiotherapy (50.4 Gy in 28 fractions), chemotherapy (weekly paclitaxel 50 mg/m² and cisplatin 25 mg/m² for 5 cycles), and toripalimab (240 mg, every 3 weeks until 12 months or disease progression). The primary endpoint was clinical complete response (cCR) rate at 3 months after CRT according to PET-CT scan and esophagogastroduodenoscopy with biopsies. Second endpoints were overall survival (OS), progression-free survival (PFS), adverse events (AEs). Exploratory endpoints included PD-L1 expression, tumor mutational burden, and genetic biomarkers as potential efficacy predictors. Results: Between November 2019 and December 2020, 42 eligible patients (2 stage II, 19 stage III, and 21 stage IVA) were included. Of them, 39 completed CRT and 3 remained under treatment. Twenty-eight patients were included for efficacy analysis (median follow-up: 7.2 months) and 42 for safety analysis (median follow-up: 5.8 months). The cCR rate was 60.7% (17/28) and the median OS and PFS were not reached. Thirty-nine patients (92.9%) had AEs, 20 patients (47.6%) experienced grade ≥3 AEs, and 1 patient (2.4%) suffered grade 5 esophageal fistula. The most common grade ≥3 AEs were lymphopenia (45.2%), neutropenia (33.3%), and anemia (28.6%), respectively. Conclusions: The addition of toripalimab to definitive CRT for locally advanced ESCC demonstrated encouraging efficacy and acceptable toxicity. The exploratory endpoints including PD-L1 expression and genetic biomarkers analyses are ongoing. Clinical trial information: NCT04005170