IntroductionRadiation-induced lung injury (RILI) is one of the most clinically-challenging toxicities and dose-limiting factors during and/or after thoracic radiation therapy for oesophageal squamous cell carcinoma (ESCC). With limited effective protective drugs against RILI, the main strategy to reduce the injury is strict adherence to dose-volume restrictions of normal lungs. RILI can manifest as acute radiation pneumonitis with cellular injury, cytokine release and cytokine recruitment to inflammatory infiltrate, and subsequent chronic radiation pulmonary fibrosis. Pirfenidone inhibits the production of inflammatory cytokines, scavenges-free radicals and reduces hydroxyproline and collagen formation. Hence, pirfenidone might be a promising drug for RILI prevention. This study aims to evaluate the efficacy and safety of pirfenidone in preventing RILI in patients with locally advanced ESCC receiving chemoradiotherapy.Methods and analysisThis study is designed as a randomised, placebo-controlled, double-blinded, single-centre phase 2 trial and will explore whether the addition of pirfenidone during concurrent chemoradiation therapy (CCRT) could prevent RILI in patients with locally advanced ESCC unsuitable for surgery. Eligible participants will be randomised at 1:1 to pirfenidone and placebo groups. The primary endpoint is the incidence of grade >2 RILI. Secondary endpoints include the incidence of any grade other than grade >2 RILI, time to RILI occurrence, changes in pulmonary function after CCRT, completion rate of CCRT, disease-free survival and overall survival. The follow-up period will be 1 year. In case the results meet the primary endpoint of this trial, a phase 3 multicentre trial with a larger sample size will be required to substantiate the evidence of the benefit of pirfenidone in RILI prevention.Ethics and disseminationThis study was approved by the Ethics Committee of Fujian Union Hospital (No. 2021YF001-02). The findings of the trial will be disseminated through peer-reviewed journals, and national and international conference presentations.Trial registration numberChiCTR2100043032.