Objective. Although B cells are implicated in the pathogenesis of systemic lupus erythematosus, the role of B cell depletion (BCD) as a treatment is controversial, given the variable benefit in human disease. This study was undertaken to test the effects of BCD therapy in a murine lupus model to better understand the mechanisms, heterogeneity, and effects on disease outcomes.Methods. (NZB ؋ NZW)F 1 female mice with varying degrees of disease severity were treated with an anti-mouse CD20 (anti-mCD20) antibody (IgG2a), BR3-Fc fusion protein (for BAFF blockade), or control anti-human CD20 monoclonal antibody (ϳ10 mg/kg each). Tissue samples were harvested and analyzed by flow cytometry. The development and extent of nephritis were assessed by monitoring proteinuria (using a urine dipstick) and by immunohistochemical analysis of the kidneys. Serum immunoglobulin levels were measured by enzyme-linked immunosorbent assay.Results. After a single injection of anti-mCD20, BCD was more efficient in the peripheral blood, lymph nodes, and spleen compared with the bone marrow and peritoneum of normal mice as well as younger mice with lupus. Since depletion of the marginal zone and peritoneal B cells was incomplete and variable, particularly in older mice with established nephritis, a strategy of sequential weekly dosing was subsequently used, which improved the extent of depletion. BAFF blockade further enhanced depletion in the spleen and lymph nodes. Early BCD therapy delayed disease onset, whereas BCD therapy in mice with advanced disease reduced the progression of nephritis. These effects were long-lasting, even after B cell reconstitution occurred, and were associated with a reduction in T cell activation but no significant change in autoantibody production.Conclusion. The lasting benefit of a short course of BCD therapy in lupus-prone mice with an intact immune system and established disease highlights the validity of this treatment approach.Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving multiple organ systems. The immunologic events triggering the onset of clinical manifestations have not been fully defined, but a central role of B cells in the pathogenesis of this disease has been established by studies performed in multiple laboratories, both in mice and in humans (1-3). Given the strong evidence supporting an abnormal B cell compartment in SLE, B cell depletion (BCD) therapy is being investigated as a potential treatment strategy. Several open-label studies, including our own, have demonstrated that BCD provides significant clinical benefit in SLE (4,5). Our studies have shown that clinical improvement after BCD therapy precedes the decline in levels of conventional serum autoantibodies, strongly supporting the notion of antibody-independent pathogenic roles of B cells.