Angiogenesis has an important role in the pathogenesis and progression of multiple myeloma (MM). MM cells secrete vascular endothelial growth factor (VEGF), which further promotes proliferation of the tumor cells. Therefore, we evaluated the anti-myeloma effect of VEGF small interfering RNA (siRNA) silencing in MM cells and whether it can be augmented by the additional inhibition of the mammalian target of rapamycin (mTOR) by everolimus. We shown that everolimus inhibits cell growth of MM cells and other leukemic cells at low concentrations in a dose-dependent manner. After transfection with VEGF siRNA we observed a reduction of cell growth and VEGF expression in all studied cell lines: OPM-2, RPMI-8226, INA-6, JURKAT and RAJI. VEGF siRNA both significantly induced apoptosis and inhibited proliferation in OPM-2 cells (P<0.0001), RPMI-8226 (P<0.0001) and in INA-6 (P<0.01) versus controls. Co-treatment with VEGF siRNA and everolimus in MM cells resulted in an exaggerated inhibition of proliferation compared with VEGF siRNA or everolimus alone (P<0.0001) and enhanced induction of apoptosis compared with VEGF siRNA alone (P<0.03). In addition, the combination of VEGF siRNA and everolimus significantly reversed P-glycoprotein expression (P<0.005) and HIF-1α expression (P<0.001) of MM cells, respectively. Our data suggest that mTOR inhibition and silencing of VEGF expression is associated with synergistic antitumor activity and this combination treatment might be a suitable strategy for new therapeutic approaches using RNA interference in MM.