Objective: To study the effect and mechanism of excision repair cross complement 1 (ERCC1) siRNA on cisplatin resistance in nasopharyngeal carcinoma cell line HNE-1/DDP. Methods: The expression level of ERCC1 in human nasopharyngeal carcinoma cells HNE-1/DDP and HNE-1 cells was measured by qRT-PCR and Western blot. Human nasopharyngeal carcinoma cell HNE-1/DDP was transfected with ERCC1 siRNA recombinant lentiviral vector and negative control vector. The interference effects were measured by qRT-PCR and Western blot. HNE-1/DDP cells transfected with ERCC1 siRNA were treated with cisplatin (DDP). MTT detection of cell proliferation, colony formation assay was used to detect cell clone formation ability, flow cytometry was used to detect the changes of cell apoptosis, Western blot was used to detect the level of C-caspase-3 and C-caspase-9 protein in the cells, at the same time, and the level of cytochrome C protein in cytoplasm and mitochondria. Results: The expression level of ERCC1 in HNE-1/DDP cells was higher than that in HNE-1 cells. ERCC1 siRNA significantly reduced the expression and transcription of ERCC1 in HNE-1/DDP cells. Both DDP and ERCC1 siRNA reduced the proliferation and clone formation ability of HNE-1/DDP cells, and increased the rate of apoptosis, promote the expression of C-caspase-3 and C-caspase-9 protein in cells, increase the level of cytochrome C protein in the cytoplasm, and reduced the level of cytochrome C protein in mitochondria. DDP treatment of HNE-1/DDP cells transfected with ERCC1 siRNA, the proliferation and cloning of cells decreased more, the rate of cell apoptosis increased more, the levels of C-caspase-3 and C-caspase-9 protein were higher in cells, the level of cytochrome C protein in cytoplasm was also higher, the level of cytochrome C protein in mitochondria decreased more. Conclusion: ERCC1 siRNA can reverse the resistance of nasopharyngeal carcinoma cell HNE-1/DDP to cisplatin, the mechanism is related to activation of mitochondrial apoptotic pathway.