Esophageal squamous cell carcinoma (ESCC) is a common malignant cancer worldwide. Despite recent improvements in surgical techniques and adjuvant therapies, the prognosis of patients with advanced ESCC remains poor. Resistance to chemoradiotherapy (CRT) remains a major cause of treatment failure for advanced ESCC patients. Here, we report that NRIP3 (nuclear receptor interacting protein 3) promotes ESCC tumor cell growth and resistance to CRT in ESCC cells by increasing and binding to DDI1 (DNA-damage inducible 1 homolog 1) and RTF2 (homologous to Schizosaccharomyces pombe Rtf2), and accelerating the removal of RTF2, which is a key determinant for the ability of cells to manage replication stress. In addition, we found that NRIP3 could increase DDI1 expression via PPARα. The NRIP3-PPARα-DDI1-RTF2 axis represents a protective molecular pathway in ESCC cells that mediates resistance to replication stress signals induced by chemoradiotherapy. In addition, elevated NRIP3 is associated with the poor clinical outcome of ESCC patients receiving radiotherapy and/or cisplatin-based chemotherapy. Our study therefore reveals that NRIP3 is a prognostic factor in ESCC and could have some predictive value to select patients who benefit from CRT treatment. A common mechanism that protects ESCC tumor cells from DNA damage induced by CRT is also revealed in this study.