Multiple myeloma (MM) is a plasma cell dyscrasia characterized by bone lesions and production of a paraprotein. B-lymphocyte stimulator (BLyS) and its receptor (BAFFR) were highly expressed on peripheral blood and bone marrow B cells in MM patients as compared to those with monoclonal gammopathy of unknown significance (MGUS) and healthy donors. Serum BLyS levels in MM patients were significantly higher than those in MGUS patients and healthy controls. BLyS expression was increased in bone marrow specimens from MM patients as ascertained by immunofluorescence. Furthermore, BLyS, together with IL-2 and IL-6, significantly promoted MM cell proliferation and BLyS receptor expression compared with that in the control group. Treatment with bortezomib, a therapeutic proteasome inhibitor induced apoptosis and repressed the proliferation of RPMI8226 and U266 cells through inhibition of NF-κB p65 and IκBα. These findings suggest that BLyS is involved in the immunopathogenesis of MM and may prove to be a hallmark of MM.