Previous studies describing the histologic elements of multi-system organ failure caused by bacterial sepsis may have been complicated by a significant interaction on tissue injury from either a preterminal low-flow state or the effects of therapy immediately before death. Therefore we evaluated the nonpulmonary histologic findings of sepsis during a 3-day period that followed cecal ligation and perforation. In this septic model, mean arterial perfusion pressures remained unchanged from baseline, systemic flows rose by 54%, and laboratory evidence of organ dysfunction including an elevation of the serum bilirubin levels and a depression of the serum total protein values was considered mild. Concurrently, development of the hyperdynamic central circulatory septic state was associated with widespread histologic changes in myocardium, striated muscle, liver, gut, and pancreas. Lesions common to these organs included high-protein interstitial and intracellular edema, mitochondrial destruction, and patchy cell necrosis. Lesions within the pancreas were exaggerated over those noted in other organs. Of all organs examined, only the liver demonstrated microvascular neutrophil accumulation. Unlike models of shock caused by sepsis, fibrin thrombi were not seen in the microvasculature of any organ. We conclude that tissue injury characterized by the accumulation of protein-rich extravascular fluid and the development of reversible and irreversible cell injury antedated significant multiple-system organ failure in this animal model of normotensive sepsis.