Background: Acute normovolemic hemodilution reduces the circulating erythrocyte mass and, thus, the hemoglobin concentration. After extreme acute normovolemic hemodilution to the critical hemoglobin concentration (Hb(crit)), oxygen demand of the tissues is no longer met by oxygen supply, and death occurs with increasing oxygen debt. The aim of the current study was to investigate whether ventilation with 100% oxygen (fraction of inspired oxygen [Fio(2)] = 1.0; hyperoxic ventilation) initiated at Hb(crit) could restore adequate tissue oxygenation and prevent death. Methods. Fourteen anesthetized pigs ventilated with room air (Fio(2) = 0.21) were hemodiluted by exchange of whole blood for 6% hydroxyethyl starch (200,000:0.5) until the individual Hb(crit) was reached. Hb(crit) was defined as the onset of oxygen supply dependency of oxygen consumption and was identified with indirect calorimetry. For the next 6 h, animals were either ventilated with an Fio(2) of 0.21 (n = 7) or an Fio(2) of 1.0 (n = 7). Results: All animals in the 0.21 Fio(2) group died within the first 3 h at Hb(crit) (ie., 6-h mortality 100%). Death was preceded by an increase of serum concentrations of lactate and catecholamines. In contrast to that, six of the seven animals of the 1.0 17102 group survived the complete 6-h observation period without lactacidosis and increased serum catecholamines (Le., 6-h mortality 14%; Fio(2) 0.21 vs. Fio(2) 1.0, P less than or equal to 0.05). After 6 h at Hb(crit), the Fio(2) was reduced from 1.0 to 0.21, and five of the six animals died within the next 3 h. Conclusion: In anesthetized pigs submitted to lethal anemia, hyperoxic ventilation enabled survival for 6 h without signs of circulatory failure.