Aim To investigate the effect of long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) on coronary heart disease (CHD) and its mechanism. Methods The expression levels of lncRNA HOTAIR, microRNA-126 (miR-126) and Polo-like kinase 4 (PLK4) in peripheral blood samples and endothelial progenitor cells (EPC) of CHD patients and healthy volunteers were detected by quantitative real-time PCR. EPC cell viability was detected by methyl thiazolyl tetrazolium assay. Apoptosis rate was detected by flow cytometry. The expressions of autophagy-related proteins LC3-Ⅱ and Beclin1 were detected by Western blot. Cell autophagy was observed by confocal microscopy. The relationship between lncRNA HOTAIR and miR-126 was analyzed by miRcode software and dual-luciferase reporter gene assay. The relationship between miR-126 and PLK4 was analyzed by TargetScan software and dual-luciferase reporter gene assay. The effect of lncRNA HOTAIR on mammalian target of rapamycin (mTOR) pathway through miR-126 in EPC was detected by Western blot. Results The expressions of lncRNA HOTAIR and PLK4 were significantly up-regulated in CHD blood samples and EPC (P＜0.01), and the expression of miR-126 was significantly down-regulated (P＜0.01). Down-regulation of lncRNA HOTAIR or PLK4 promoted autophagy in EPC, and inhibited CHD progression. Up-regulation of lncRNA HOTAIR inhibited EPC autophagy and promoted apoptosis through miR-126.The lncRNA HOTAIR activated the mTOR pathway in EPC via miR-126. Conclusion HOTAIR/miR-126/PLK4 axis mediates autophagy in EPC and affects CHD via mTOR signaling pathway.