Clinical resistance to chemotherapeutic agents is one of the major hindrances in the treatment of humancancers. EHZ2 is involved in drug resistance and is overexpressed in drug-resistant cancer cell lines. In this study,we investigated the effects of EHZ2 on cisplatin -resistance in A549/DDP and AGS/DDP cells. EHZ2 mRNA andprotein were found to be significantly overexpressed in A549/DDP and AGS/DDP cells, compared to parentalcells. EHZ2 siRNA successfully silenced EHZ2 mRNA and protein expression. Proliferation was inhibited anddrug resistance to cisplatin was improved. Flow cytometry showed that silencing of EHZ2 arrested A549/DDPand AGS/DDP cells in the G0/G1 phase, increasing apoptosis, rh-123 fluorescence intensity and caspase-3/8activities. Silencing of EHZ2 also significantly reduced the mRNA and protein expression levels of cyclin D1 andMDR1,while up-regulating p15, p21, p27 and miR-218 in A549/DPP cells. Furthermore, silencing of EHZ2 alsosignificantly increased the expression level of tumor suppressor factor miR-218. We also found down-regulatingEHZ2 expression increased methylation in A549/DDP and AGS/DDP cells. This study demonstrates that drugresistance can be effectively reversed in human cisplatin-resistant lung and gastric cancer cells through deliveryof siRNAs targeting EHZ2.