OBJECTIVE: Non-small cell lung cancer (NSCLC), as an ordinary malignant tumor, presents with high death rate and poor prognosis. Few literatures have explored the association between NSCLC development and lncRNAs expression. This study focuses on the important role of a novel lncRNA TRPM2-AS in the development of chemo-resistance in NSCLC. MATERIALS AND METHODS: The expression level of lncRNA TRPM2-AS was identified by using qRT-PCR assay. The apoptosis rate and the alteration of the cell cycle were detected by the flow cytometric analysis. Cell Counting Kit-8 assay (CCK8) was utilized for detecting chemo-sensitivity of the cisplatin-resistant A549/DDP cells. The p53 and p66shc protein levels were detected by Western blotting assay. RESULTS: A549/DDP cells presented remarkably higher expression of lncRNA TRPM2-AS than paired A549 cells. Moreover, re-sensitization to cisplatin was seen in A549/DDP cells after lncRNA TRPM2-AS knockdown. On the contrary, the sensitivity of lncRNA TRPM2-AS-overexpressed A549 cells to cisplatin decreased obviously when compared with the control. Furthermore, downregulated lncRNA TRPM2-AS induced cell apoptosis and altered cell cycle distribution through activating the p53-p66shc pathway. CONCLUSIONS: We suggest that lncRNA TRPM2-AS participates in the resistance of NSCLC cells to cisplatin, which may provide a new therapeutic target of NSCLC.