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Sepsis is an intriguing pathological condition associated with many complex metabolic and physiological alterations. In this review a novel hypothesis in the pathophysiology of oxygen metabolism during sepsis is explored. It is proposed that the hypermetabolic response to sepsis results from enhanced reactive oxygen generation by phagocytes. Reactive oxygen detoxification by host enzyme systems subsequently leads to alterations in oxidative metabolism. The similarities between the metabolic consequences of reactive oxygen metabolism and the metabolic changes observed during sepsis are outlined. A unified concept is presented to help explain the pathophysiological changes in oxygen metabolism during sepsis.