This study was aimed to investigate the apoptosis induced by bortezomib combined with As(2)O(3) in APL cell line NB4 and its mechanism. The apoptotic cells were detected by flow cytometry with Annexin V/propidium iodide double staining; the morphology of apoptotic cells was observed by Hoechst staining, Western blot was used to measure activation of caspase-3 and -9 as well as expression of NOXA; the siRNA technique was used to specifically silence NOXA gene; the lipofectamine 2000 was used to transfect pEGFP-Noxa plasmid and pEGFP vacant vector. The results showed that the bortezomib combined with As(2)O(3) could induce significant apoptosis of NB4 cells and activation of caspase 3 and caspase 9, but As(2)O(3) (0.5 µmol/L) alone could not cause marked activation of caspase cascade and apoptosis of NB4 cells. The expression level of NOXA in NB4 cells induced by bortezomib combined with As(2)O(3) was up-regulated; the activation level of caspase-3 and apoptotic rate of NB4 cells treated by bortezomib combined with As(2)O(3) decreased after specifically silencing the NOXA gene. The high expression of NOXA induced by transfection of plasmid could enhance the caspase 3 activity induced by As(2)O(3) alone. It is concluded that bortezomib can enhance sensitivity of NB4 cells to apoptosis induced by As(2)O(3) which may be related with up-regulation of proapoptotic protein NOXA.