Abstract: Objective To investigate the relationship between DR4 gene promoter methylation and tumor necrosis factorrelated apotosisinducing ligand（TRAIL） resistant in lung adenocarcinoma. Methods Lung adenocarcinoma cells A549, LTEP-α-2 untreated by 5-aza-2'-deoxycytidine（5-Az-CdR） and treated by 5-Aza-CdR for 3 days were selected. Cell counting kit-8（CCK-8）assay was used to determine the inhibitory rate of cell proliferation，and the cell morphological was observed by inverted microscope. The apoptosis of cells was detected by flow cytometry. The protein and mRNA expression levels of DR4 gene in lung adenocarcinoma cell lines（A549， LTEP-α-2） were detected by Western blotting and RT-PCR methods. The methylation of DR4 gene promoter region was examined by methylation-specific PCR（MSP）. Results Lung adenocarcinoma cells（A549， LTEP-alpha-2） were highly resistance to TRAIL at the low concentration. After increasing the concentration of TRAIL（15.625, 31.25, 62.5, 125, 250, 500 μg/ml）， cell growth was inhibited and existed in a dose and time dependent after 24 and 48 hours. After cells were treated by 5-Aza-CdR， the inhibitory effects of lung adenocarcinoma cell treated by TRAIL was significantly higher than before treatment（P＜0.05）.The morphology of the cells was round， shrinkage and even shedding under the microscope. After cells were treated by 125 μg／ml 5-Aza-CdR， the apoptosis rate of lung adenocarcinoma cells induced by TRAIL was significantly much more higher than before treatment（P＜0.05）. Expressions of DR4 mRNA and protein in A549， LTEP-α-2 cells were low， and DR4 gene promoter was methylation state. After cells were treated by 5-Aza-CdR， the expressions of DR4 mRNA and protein were more increased significantly than before treatment（P＜0.05）， and DR4 gene promoter was unmethylated. Conclusion 5-Aza-CdR can reverse DR4 gene promoter methylation state， regulating the level of gene expression， increasing TRAILinduced apoptosis in lung cancer cells， furthermore， reversing TRAIL resistance. Therefore， 5-Aza-CdR combined with TRAIL may be a new strategy for the treatment of lung adenocarcinoma.