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Hypoxia has a dual effect on ventilation: an initial period of hyperventilation, the acute hypoxic response, is followed after 3–5 min by a slow decline, the hypoxic ventilatory decline. Because of hypoxic ventilatory decline, subsequent acute hypoxic responses are depressed. In this study, the influence of a sedative concentration of propofol on ventilation was studied if hypoxia was sustained and intermittent.Ten healthy young male volunteers performed two hypoxic tests without and with a target controlled infusion of propofol. The sustained hypoxic test consisted of 15 min of isocapnic hypoxia followed by 2 min of normoxia and 3 min of hypoxia. The test of hypoxic pulses involved six subsequent exposures to 3 min hypoxia followed by 2 min of normoxia. The bispectral index of the electroencephalogram was measured to obtain an objective measure of sedation.Blood propofol concentrations varied among subjects but were stable over time (mean blood concentration 0.6 μg/ml). The sustained hypoxic test showed that propofol decreased acute hypoxic response by ∼50% and that the magnitude of hypoxic ventilatory decline relative to acute hypoxic response was increased by > 50%. Propofol increased the depression of the acute hypoxic response after 15 min of hypoxia by ∼25%. In control and propofol studies, no hypoxic ventilatory decline was generated during exposure to hypoxic pulses. The bispectral index–acute hypoxic response data suggest that subjects were either awake (with minimal effect on acute hypoxic response) or sedated (with 50–60% reduction of acute hypoxic response).The depression of acute hypoxic response results from an effect of propofol at peripheral or central sites involved in respiratory control or secondary to the induction of sedation or hypnosis by propofol. The relative increase in hypoxic ventilatory decline is possibly related to propofol’s action at the γ-aminobutyric acid A (GABAA) receptor complex, causing increased GABAergic inhibition of ventilation during sustained (but not intermittent) hypoxia.