We have studied the circulatory response to 100% O2 at 1 and 3 atm, using unanesthetized rabbits in which a systemic artery and the right heart had been cannulated previously. One group of animals served as controls; the other was infused with a flurocarbon emulsion that boosted blood O2 solubility to approximately 5 ml.100 ml-1.atm-1. Exposure to hyperoxia caused an identical sustained rise in arterial PO2 in both groups. O2 uptake was measured during normobaric exposure to 100% O2 and was found to be the same as in control conditions. There was an immediate rise in right heart PO2, more marked in infused animals, but this increase was only temporary, and PO2 dropped, while the right heart-arterial PCO2 difference rose, indicating a gradual fall in cardiac output. This readjustment occurred at a faster rate in the infused animals, a difference that led us to conclude that the peripheral response to hyperoxia is influenced by factors other than arterial PO2. The pronounced decrease in cardiac output seen in infused rabbits was accompanied by lactic acidosis, implying that some of the animals' tissues were becoming hypoxic in the presence of arterial hyperoxia.