Despite recent advances in the treatment of myelodysplastic syndrome (MDS), single-agent clinical effects remain unsatisfactory, and decitabine monotherapy is also associated with a relatively low rate of complete remission. To study the combined effects and mechanism of decitabine (DAC) and arsenic trioxide (ATO) on the human myelodysplastic cell line SKM-1,we used the MTS assay and CalcuSyn software to determine the cytotoxicity and potential synergistic effects, respectively. Furthermore, we determined apoptosis and measured the mRNA expression level of two genes that are considered main regulators of the apoptosis process. The results showed that DAC and/or ATO can inhibit the proliferation of SKM-1 cells and demonstrated significant synergy between the two agents (CI < 1). Additionally, combination of 2.5 μmol/L DAC and 5 μmol/L ATO led to a significantly higher apoptosis rate and more significantly decreased the Bcl2/Bax ratio than either compound alone (P < 0.001). Based on the observations of this study, we suggest that combined administration of these two drugs might be considered a novel therapeutic regimen for treating MDS.