Altered B cell function is important in the pathogenesis of rheumatoid arthritis (RA). In this report, we show that patients with active RA have an increased frequency of CD32B low/neg cells in the CD27(+)IgD(-) memory B cell subset and that these changes are associated with phenotypic and functional B cell activation. Studies using PBMCs from healthy donors revealed that downregulation of CD32B on B cells is mediated by CD40-CD40L interactions and is potentiated by IL-4 and inhibited by both IL-10 and IL-21. These findings appear physiologically relevant because CD4 T cell expression of CD40L correlated with the frequency of CD32B low/neg cells in the CD27(+)IgD(-) memory B subset in patients with RA. Our data support a model in which high levels of CD40L, present on circulating T cells in patients with RA, causes B cell activation and CD32B downregulation, resulting in secondary protection of memory B cells from CD32B-mediated cell death.