background: Overexpression of the enhancer of zeste homolog 2 (EZH2) protein has been found in broad range of cancer types, including non-small cell lung cancer (NSCLC). Nevertheless, the mechanisms by which EZH2 becomes overexpressed in NSCLC remain unclear. MicroRNAs (miRNAs) can regulate target gene expression through translational control. In this study, we investigate whether miRNA (miR-101) regulates EZH2 expression in NSCLC. methods: We evaluated the expression of miR-101 and EZH2 in 20 matched NSCLC and adjacent nontumor lung tissues by reverse-transcriptase polymerase chain reaction and immunohistochemistry, respectively. Luciferase reporter assay was used to determine whether miR-101 directly targets EZH2. To assess the effect of miR-101 on NSCLC biological behavior, cell proliferation, invasion, and response to chemotherapy were analyzed using NSCLC cells transfected with miR-101 mimics or transfected with specific small interfering RNA to deplete EZH2 (small interfering RNA-EZH2). results: Reduced expression of miR-101 was associated with overexpression of EZH2 in NSCLC tumor tissues. Transfection of miR-101 mimics significantly suppressed the activity of the luciferase reporter containing wild type but not mutant EZH2 3'-UTR and decreased EZH2 expression in NSCLC cell lines. Furthermore, enforced expression of miR-101 or knockdown of EZH2 led to reduced NSCLC cell proliferation and invasion and sensitized cancer cells to paclitaxel-mediated apoptosis through inducing expression of the proapoptotic protein Bim. conclusions: miR-101 inhibits cell proliferation and invasion and enhances paclitaxel-induced apoptosis in NSCLC cells, at least in part, by directly repressing EZH2 expression. Therapeutic strategies to rescue miR-101 expression or silence EZH2 may be beneficial to patients with NSCLC in the future.