Infection with Schistosoma mansoni remains a major public health problem in many resource-limited countries in the world. There are costs and logistical challenges associated with chemotherapy and sanitation-based control, and a vaccine might be needed as an additional tool for long-term control or elimination [1]. However, vaccine development has been hindered by limited translational data from studies in laboratory animals and an inadequate understanding of the protective immune mechanisms in humans [2]. Recent data showing that a proportion of adults occupationally exposed to S. mansoni can become more resistant to reinfection [3] have encouraged continued research into a vaccine. Studies in the human host to further characterize the immune responses that correlate with protection should help in vaccine development. In many field-based studies, high levels of parasite-specific IgE correlate with resistance in schistosomiasis [4 - 6], yet our understanding of the mechanisms of IgE regulation is limited. Remarkably, although B cells are the producers of IgE, little is known about human B cell function in schistosomiasis. In mice, B cells have been shown to play an important role in antiparasite immunity, not only as antibody producers but also in promoting an optimal and sustained T cell response [7]. It remains important to define the roles that human B cells play in immunity to schistosomiasis. IgE most likely exerts in vivo effector and regulatory function(s) through its high-affinity (FceRI) and/or low-affinity (FceRII or CD23) receptors on myeloid cells [8]. CD23 is also expressed by B cells. In some settings, CD23-bound IgE cross-linked by antigen activates B cells, and it has been shown to regulate IgE production. However, although CD23 may exercise opposing roles in IgE immune responses in mice [8, 9], it appears to be a positive regulator in humans and may have an important role in human immunology [10]. IgE-antigen complexes also enhance human B cell antigen presentation to T cells in vitro, although the specific intracellular mechanisms have not been detailed [9, 11, 12]. Thus, the production and regulation of IgE may be mediated in part through CD23+ B cells [8, 12-17]. The mechanisms of high IgE output at the level of the B cell are not well characterized in schistosomiasis, and it is not understood why some individuals develop high IgE levels and others do not, despite generally comparable levels of exposure. We have studied CD23 expression on B cells in a unique setting involving the development of demonstrable resistance to natural reinfection by S. mansoni in humans. We show that levels of both CD19+CD23+ B cells and circulating soluble CD23 (sCD23) correlate with the development of resistance to reinfection and with other indicators of resistance, such as eosinophilia, during a defined period of multiple praziquantel treatments and reinfections.