The application of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is limited by drug resistance in non-small cell lung cancer (NSCLC). Long non-coding RNAs (lncRNAs) are known to be involved in tumor development and metastasis, as well as chemotherapy resistance. To gain insight into the molecular mechanisms of EGFR-TKIs resistance, EGFR-TKIs‑sensitive and ‑resistant human lung cancer cells were analyzed by lncRNA microarray. In the present study, we found a total of 22,587 lncRNAs expressed in lung cancer cells. Of these, the expression level of 1,731 lncRNAs was upregulated >2-fold compared with gefitinib-sensitive cells while that of 2,936 was downregulated. Bioinformatics analysis (GO and pathway analyses) revealed that some classical pathways participating in cell proliferation and apoptosis were aberrantly expressed in these cells (P-value cut-off was 0.05). Enhancer-like lncRNAs and their nearby coding genes were analyzed. Six lncRNAs were identified as potential enhancers. Several lncRNAs were validated in lung cancer cell lines using RT-qPCR. To the best of our knowledge, the results showed for the first time that differentially expressed lncRNAs responded to EGFR-TKIs resistance in NSCLC cells. LncRNAs may therefore be novel candidate biomarkers and potential targets for EGFR-TKIs therapy in the future.