Shiga toxin (Stx) and lipopolysaccharide (LPS) both participate in the pathogenesis of post-diarrheal hemolytic uremic syndrome (HUS), yet little is known about the factors that modulate the host response to these toxins. We have previously shown that the baboon develops HUS if 100 ng/kg of purified Stx-1 is administered rapidly as a single bolus, but not if it is given as four 25-ng/kg doses every 12 h. We therefore used this baboon model to study the response to small intravenous doses of Stx-1, with and without the co-administration of LPS. The co-administration of two 1-mg/kg doses of LPS (given at 0 and 24 h) and four 25-ng/kg doses of Stx-1 (given at 0, 12, 24, and 36 h) resulted in HUS, but the administration of either toxin separately did not. The development of HUS was associated with a rise in urinary, but not plasma concentrations of TNF, and a rise in both urinary and plasma concentrations of IL-6 and IL-8. We speculate that LPS is not required for disease expression in the human, but that it can augment the response to otherwise subtoxic amounts of Stx and this augmentation may be mediated by LPS-induced cytokine release.