Objective Multiple myeloma (MM) cells are extremely resistant to drug-induced apoptosis due to both intrinsic- and bone marrow (BM) microenvironment–dependent drug resistance particularly supported by bone cells. Growing evidence suggest that the osteoclast inhibitor zoledronic acid (ZOL) exerts both indirect and direct anti-tumoral effects, including an in vitro proapoptotic effect on MM cells, although this property has not yet been clearly observed in MM patients. Materials and Methods In this study, we attempt to better define the cytotoxic effect of ZOL on MM cells in order to identify novel drug combinations able to potentiate its proapoptotic effect. Results Our data shows that ZOL at concentrations ranging from 10 to 100 μM was able to induce MM cell apoptosis overcoming the prosurvival effect of both stromal cells and osteoclasts and independent of the intrinsic bortezomib resistance of MM cells. Interestingly, we found that the capacity of ZOL to induce apoptosis in bortezomib-resistant cells was associated with a downregulation of the proapoptotic molecule myeloid cell leukemia-1. A transcriptional analysis by microarray was also performed to identify genes specifically modulated by ZOL in bortezomib-resistant MM cells. Finally, we show an additive effect of arsenic trioxide on apoptosis when used in combination with ZOL. Conclusions Our in vitro data suggest that the use of ZOL at appropriate doses could be explored clinically in bortezomib-resistant MM patients and combined with arsenic trioxide to increase its proapoptotic effect.