Abstract Key events in T cell-dependent antibody responses, including the formation of germinal centers and affinity selection, are dependent on the ability of B cells to capture antigen and present it to follicular helper T cells. Despite its importance, little is known about the regulation of this critical B cell function. Here we show that although TLR9 signaling induced B cell proliferation, secretion of cytokines and IgM, it blocked the ability of antigen-specific B cells to capture, process and present antigen. In the presence of the TLR9 agonist, CpG, B cells were less able to form synapses with antigen-containing membranes and to pull antigen from them. CpG also diminished the ability of the BCR to deliver internalized antigen to antigen processing compartments resulting in fewer MHC-peptide complexes on the B cell surface. Additionally CpG blocked the BCR-induced increases in the expression of both MHC class II and important co-receptors, including CD86, resulting in the inability of B cells to activate antigen-specific CD4+ T cells. A principle component analysis of RNA seq data showed little overlap between B cells stimulated through the BCR or TLR9 alone or together indicating that TLR9 antagonism of BCR-dependent antigen presentation is through the activation of a novel transcriptional program. In a chimeric mouse model and in a human clinical trial the TLR9 agonist, CpG, enhanced the magnitude of the antibody response to a protein vaccine but failed to promote affinity maturation. Thus, TLR9 signaling may enhance the magnitude of an antibody response at the expense of the ability of B cells to engage in germinal center events that are highly dependent on antigen capture and presentation.