Schistosomiasis is caused by parasitic trematodes. Individuals can accumulate hundreds of intravascular worms, which secrete a myriad of antigenic molecules into the bloodstream. Some of these molecules suppress immunity to microbial Toll-like receptor (TLR) ligands, such as lipopolysaccharides, which may increase host susceptibility to coinfecting pathogens. We show that schistosomiasis is associated with extremely high levels of endotoxemia as well as high mobility group 1, an endogenous inflammatory TLR ligand, in the absence of other coinfected pathogens. Circulating B cells express surface TLR2 and TLR4, reflecting systemic exposure to microbial ligands. Bacterial translocation may occur with schistosomal egg movement from the vascular to the gut and other routes, such as the skin during infection. Our report suggests that immunosuppressive schistosome antigens may have evolved to curb inflammatory responses to the high antigenic burden of translocated bacteria products and endogenous TLR ligands that arise during parasite exposure and inflammation.