Background <p>Concurrent chemoradiotherapy (CCRT) is the standard treatment for unresectable esophageal squamous cell carcinoma (ESCC). However, its local control rate and overall survival (OS) gain are limited, resulting in a 5-year survival rate of only 20%. Nevertheless, combined immunotherapy (IT) and chemotherapy has demonstrated efficacy in patients with advanced esophageal cancer. This study explored a novel therapeutic strategy and aimed to evaluate the efficacy and safety of CCRT + IT versus CCRT alone in patients with locally advanced unresectable ESCC.</p> Methods <p>In this retrospective cohort study, data from 106 patients with locally advanced ESCC who underwent CCRT at the Department of Radiotherapy of the First Affiliated Hospital of Guangxi Medical University, between July 2019 and December 2022, were collected and analyzed. Among them, 60 patients received CCRT combined with IT (CCRT + IT group) and 46 patients received CCRT only (CCRT group). The prognosis and adverse events (AEs) were compared between the two groups.</p> Results <p>The baseline clinical characteristics were similar between the CCRT + IT and CCRT groups. However, the objective response rate (ORR) of the primary tumor was significantly better in the CCRT + IT group than in the CCRT group (76.7% vs. 52.2%; <i>p</i> = 0.008). Compared with the CCRT group, the 1-year progression-free survival (PFS) rate and median PFS were significantly higher in the CCRT + IT group (1-year PFS: 66.7% vs. 41.3%, <i>p</i> = 0.009; median PFS: 17.1 months vs. 9.8 months, <i>p</i> = 0.030). Additionally, both the OS rate and median OS were higher in the CCRT + IT group than in the CCRT group (1-year OS: 80.0% vs. 58.7%, <i>p</i> = 0.017; median OS: 19.6 months vs. 14.2 months, <i>p</i> = 0.087). The incidence of grade ≥ 3 AEs was low and did not significantly differ between groups.</p> Conclusions <p>CCRT + IT is a promising treatment for locally advanced ESCC, offering remarkable efficacy and manageable toxicity.</p>