This study was purposed to explore the effects of hyperbaric oxygen (HBO) combined with adriamycin (ADM) on inducing apoptosis of multidrug resistant cells line K562/A02. The cell apoptosis and expression of caspase-3 activity were analyzed by flow cytometry and transmission electron microscopy; the expression levels of HIF-1α, BCL-2 and BAX mRNA were detected by quantitative real time PCR; the caspase 8 activity was determined by using caspase 8 kit; the expression level of P-gp was detected by Western blot. The results showed that the apoptosis rate of K562/A02 cells in combination group (0.2 MPa HBO + ADM) was higher than that in ADM group [(47.36 ± 3.87) % vs (28.51 ± 1.09) %], the difference was statistical significant (p < 0.05); the expression levels of HIF-1α mRNA, P-gp and BCL-2 in combination group were lower than those in ADM group, there were significant differences (p < 0.05); the activities of BAX, caspase 3 and caspase 8 proteins in combination group were higher than those in ADM group, the difference was statistical significant (p < 0.05). It is concluded that 0.2 MPa HBO combined with ADM can reverse the drug-resistance of K562/A02 cells to ADM, enhance the apoptosis rate of cells. The molecular mechanism may be related with down-regulation of P-gp and BCL-2 expression, and up-regulation of caspase-3 and caspase-8 activities by HIF-1α.