Patients with multiple myeloma (MM) have increased bone marrow angiogenesis, but the angiogenic properties of myeloma cells and the mechanism of MM-induced angiogenesis have not been completely clarified. Notch1 signal has been identified as a critical factor in the regulation of vessel formation. However, the role of Notch1 in the angiogenesis of MM is unclear. We constitutively overexpressed active Notch1 in RPMI8226 cells to explore the effect of Notch1 signaling on cell growth and tumor angiogenesis in vivo and in vitro. We found that Notch1 overexpression promoted myeloma cells growth and increased drug resistance. Moreover, vascular endothelial growth factor (VEGF) expression was increased. Finally, our in vitro results were supported by the in vivo finding in human myeloma xenograft Nonobese diabetic/severe combined immunodeficient (NOD/SCID) models. Notch1 overexpression in MM cells resulted in up-regulation of VEGF expression, promotion of tumor growth, and increased microvessel density (MVD). Our study suggests that Notch1-induced angiogenesis is partly due to activation of VEGF pathway.