The aim of this study was to detect the efficiency of arsenic trioxide (ATO) alone or together with bortezomibto inhibit proliferation and induce apoptosis in a multiple myeloma (MM) RPMI 8266 cells. Mechanisms of actionwere also investigated. RPMI 8266 cells were treated with ATO alone and in combination with bortezomib for24 hours, and cell viability was assessed by modified MTT. Annexin V-F1TC and PI staining was used to detectthe apoptosis rate and cell cycling was investigated by flow cytometry, along with expression of cell surfacedeath receptor-4(DR4) and death receptor-5 (DR5). Western blotting was applied to detect the expression ofbcl-2, caspase-3, caspase-8, and caspase-9. As a result, the ATO combined with bortezomib group showed moreinhibition of RPMI 8266 cell viability than theATO group. Expression of DR4 and DR5 on the cell surfaces,and the apoptosis rate were increased after treatment by ATO alone or combined with bortezomib. The cellsappeared to arrest in G2/M phase after treatment. Expression of bcl-2 was more significantly decreased in thecombination group, and that of caspase-3, caspase-8 and caspase-9 was significantly increased as well. Therefore,bortezomib can enhance ATO actions to induce apoptosis in RPMI 8266 cells, with decrease in expression ofbcl-2 and increase of caspase-3, caspase-8 and caspase-9 proteins.