The effects of oxygenation and hypercapnia on diaphragmatic function and central drives were assessed during the development of respiratory failure in anesthetized unbound spontaneously breathing rabbits. Oxygenation significantly altered endurance times, whereas hypercapnia had no effect. Isolated high-frequency contractile fatigue of the diaphragm was found in hyperoxic animals; all other animals had no evidence of contractile fatigue. Oxygenation and hypercapnia did not significantly alter the response of breathing frequency or duty cycle to loading. In all animals, there was a falloff in the intensity of central drive before apnea, with intensity of central drive remaining submaximal throughout loading. Oxygenation significantly altered the time and/or load at which drive intensity fell off, although critical blood gas levels were not associated with the falloff in intensity. We conclude that oxygenation influences the development of respiratory failure during inspiratory loading but does not directly explain the alterations is central drive. On the other hand, hypercapnia has no direct effect on respiratory muscle function or central drives during loading to respiratory failure. When the effects of hypoxemia are obviated by hyperoxia, high-frequency contractile fatigue may occur.