Background: Concurrent chemoradiotherapy (CCRT) is the standard therapy for locally advanced unresectable esophageal squamous cell cancer (ESCC)，However, some patients cannot tolerate or are unwilling to CCRT. The aim of this phase II trial was to assess the efficacy and safety of the tirelizumab combined with radiotherapy in patients of locally advanced unresectable ESCC. Methods: Key eligibility criteria were as follows: ESCC of clinical stage Ⅱ-Ⅳa; aged 18 to 90 years; cannot tolerate or are unwilling to CCRT; ECOG performance status 0 or 1; and performed radiotherapy: Involvement field irradiation, nodal GTV (GTVn) (regional lymphatic metastasis) radiotherapy dose 60Gy, the esophageal gross tumor volume (GTVt) radiotherapy dose 50Gy, if the gastroscope pathology is completely relieved, otherwise it is 60Gy. All patients registered before radiotherapy. The patient received concurrent therapy with tirelizumab (200mg every time, 3-week cycle), until the disease progresses or clinical benefits are lost (the longest time is 12 months). The primary endpoint was the esophageal gross tumor pathological complete remission rate (pCR). Results: Between 01 August 2021 and 31 December 2022, 31 patients were enrolled, and 27 completed radiotherapy and at least two times of tirelizumab treatment. Data cutoff date was 31 January 2023, median follow-up time among survivors after radiotherapy was 9 months (range 4-20). The esophageal gross tumor pCR rate was 66.7% (95% CI, 14.3%-52.3%) and treatment-related adverse events (TRAEs) of low severity (grade 1-2, 48.1%; grade 3, 7.4%; grade 4-5, no). No treatment-related mortality occurred. Two (7.4%) patients had tumor recurrence and two (7.4%) patients died (Infection and heart disease). The 1-year PFS rate, median PFS and median OS had not been reached yet. For locally advanced unresectable ESCC that can't receive CCRT, the combination of tirelizumab and radiotherapy shows promising efficacy and acceptable toxicity, providing a feasible and effective choice. The research of long-term survival analysis is under way. Conclusions: Concurrent radiotherapy with tirelizumab shows promising efficacy and controllable safety for patients with locally advanced ESCC who are unable or unwilling to undergo CCRT, and warrants further evaluation in larger studies. Clinical trial information: ChiCTR2100053182.