Waldenstrom’s macroglobulinemia (WM) is a serious and frequently fatal disorder characterized by the production of a monoclonal IgM protein, a lymphoplasmacytic infiltrate in the bone marrow, and associated symptoms including anemia, lymphadenopathy and hyperviscosity. Many of the mechanisms leading to this disease are not yet known. It is clear, however, that there is dysregulation of the balance between cell proliferation and programmed cell death. BLyS (B-lymphocyte stimulator) is a TNF family member expressed by monocytes, neutrophils, macrophages, and dendritic cells. BLyS has been shown to be critical for maintenance of normal B cell development and homeostasis, and has been found to stimulate lymphocyte growth. BLyS is overexpressed in a variety of B-cell malignancies and has been shown to inhibit apoptosis in malignant B-cells. Studies of the effects of BLyS on B cell physiology have shown that it also regulates immunoglobulin secretion. In previous work, we have shown that malignant B cells from patients with WM are able to bind soluble BLyS and variably express the BLyS receptors, BAFF-R, TACI and BCMA. We also found expression of BLyS in bone marrow specimens by immunohistochemistry and elevated serum BLyS levels in patients with WM. The goal of this study was to determine the functional role of BLyS-receptor ligand system in Waldenstrom’s macroglobulinemia and its relevance to the increased immunoglobulin production seen in this disease. Using cells from WM patients, we first examined the ability of BLyS to increase the secretion of IgM by malignant B cells. BLyS, alone or in combination with cytokines that induce plasmacytic differentiation and immunoglobulin production (IL-2, IL-6, IL-10 and IL-12), was found to increase IgM secretion by malignant B cells. Mean baseline IgM levels significantly increased in cells treated with BLyS (p=0.03), cytokines (p=0.0002) and a combination of BLyS and cytokines (p<0.0001). We then determined the effect of BLyS on the survival of malignant B cells using Annexin-V/PI staining. Compared to cells cultured in media alone, BLyS was found to increase viability of malignant B cells from WM patients. Cell viability was normalized relative to the media-alone control and the median relative viability increased significantly compared to controls (median increase 41.2%; range 8 – 46%). Next, we examined the ability of BLyS to modulate cell proliferation using thymidine incorporation. Using WM patient samples, BLyS was found to significantly enhance the proliferation of malignant B cells (p=0.0002). Furthermore, addition of anti-Ig antibody further enhanced the ability of BLyS to promote the proliferation of malignant B cells (p<0.0001). In summary, we have demonstrated that BLyS enhances IgM secretion by malignant B cells from patients with Waldenstrom’s macroglobulinemia. We have also demonstrated the ability of BLyS to enhance the survival and proliferation of malignant B cells. Strategies to inhibit BLyS may potentially have therapeutic efficacy in Waldenstrom’s macroglobulinemia.