Background: There is few high-level prospective randomized studies and international consensus guideline on treatment in elderly patients with inoperable locally advanced esophageal squamous cell carcinoma (LAESCC). Double-agent intravenous chemotherapy concurrent with radiotherapy is the standard of care for LAESCC. However, it’s based on clinical trials that only enrolled patients ≤ 75 years old and infeasible in elderly patients. Oral S-1 plus concurrent radiotherapy for elderly ESCC showed tolerable toxicity and survival benefit compared with radiotherapy alone. While, the 3-year overall survival (OS) rate is limited about 40%. Therefore, it urgently needs find new treatment strategies to further improve the efficacy in elderly ESCC patients. Tislelizumab, the antii-PD-1 antibody, has recently been proved in the first- and second-line standard treatment for advanced ESCC. It shows mild toxicities and might be well-tolerated in the elderly. Here, we conducted the first clinical trial to assess the efficacy and safety of tislelizumab plus concurrent chemotherapy (CCRT) versus CCRT for elderly patients with inoperable LAESCC. Methods: The study is an open label, multicenter, parallel-controlled, investigator-initiated phase II clinical trial in elderly patients with inoperable LAESCC. We plan to enroll 136 elderly patients with LAESCC who will be randomly divided into two groups: tislelizumab combined with CCRT group (tislelizumab + radiotherapy + S-1) and CCRT group (radiotherapy + S-1). Tislelizumab is given intravenously on the first day of CCRT at the dose of 200 mg once every 3 weeks (Q3W). Radiotherapy is delivered at 50.4 Gy/1.8 Gy/28 fraction (5 times per week). S-1 is orally given at the dose of 40-60 mg from day1 to day14 and day 22 to 35. We will evaluate the efficacy and safety during the treatment and follow-up period until disease progression, death or the end of the trial. Considering the median progression free survival (PFS) is 16 months in elder receiving CCRT in history studies, we expect the median PFS would be 28 months at the hazard ratio of 0.57. The final sample size consists in 136 patients by 1:1 randomized in the two groups with 80% power and one-sided alpha and calculating for a 10% dropout rate. The primary endpoint is PFS. Secondary endpoints include OS, objective response rate, duration of objective response and severity of adverse events. Fresh or archival tumor tissues and peripheral blood samples will be used in the exploratory studies. This trial started on October 10, 2023 and has enrolled 19 patients till February 1, 2024. Clinical trial information: NCT06061146.