Objectives: Optimizing oxygen delivery is an important part of the hemodynamic resuscitation of septic shock, but concerns have been raised over the potentially deleterious effects of hyperoxia. We evaluated the impact of hyperoxia on hemodynamics, the microcirculation, and cerebral and renal metabolism in an ovine model of septic shock. Design: Randomized animal study. Setting: University hospital animal research laboratory. Subjects: Fourteen adult female sheep. Interventions: After induction of fecal peritonitis, sheep were randomized to ventilation with an Fio(2) of 100% (n = 7) or an Fio(2) adjusted to maintain Pao(2) between 90 and 120 mm Hg (n = 7, control). All animals were fluid resuscitated and observed until death. Measurements and Main Results: In addition to hemodynamic measurements, we assessed the sublingual microcirculation, renal and cerebral microdialysis and microvascular perfusion, and brain tissue oxygen pressure. Hyperoxic animals initially had a higher mean arterial pressure than control animals. After onset of shock, hyperoxia blunted the decrease in stroke volume index observed in the control group. Hyperoxia was associated with a higher sub-lingual microcirculatory flow over time, with higher cerebral perfusion and brain tissue oxygen pressure and with a lower cerebral lactate-to-pyruvate ratio than in control animals. Hyperoxia was also associated with preserved renal microvascular perfusion, lower renal lactate-to-pyruvate ratio, and higher Pao(2)/Fio(2) ratio. Conclusions: In this acute peritonitis model, hyperoxia induced during resuscitation provided better hemodynamics and peripheral microvascular flow and better preserved cerebral metabolism, renal function, and gas exchange. These observations are reassuring with recent concerns about excessive oxygen therapy in acute diseases.