In humans and cats the ventilatory response to 30 min of isocapnic hypoxia is biphasic with an initial increase followed by a decrease, termed "hypoxic depression." In humans, 30 min of hypoxia reduces the initial response to a subsequent hypoxic exposure. These experiments were to determine whether the same occurred in cats. Cats were studied while awake. End-tidal Po2 and Pco2 were measured by sampling tracheal gas, and ventilation was measured plethysmographically. In seven cats we measured ventilatory responses to two 30-min periods of isocapnic hypoxia (end-tidal Po2 = 60-65 Torr) separated by 5 min of room air breathing. The first hypoxic response was biphasic, with ventilation increasing to 149% of control at 5 min and decreasing to 117% of control at 25 min. During the second exposure, ventilation was 119% of control at 5 min and 113% of control at 25 min; 30 min of hypoxia depressed the subsequent hypoxic response. Hypoxic depression outlasted the hypoxia, suggesting that it was mediated by relatively slow neurochemical events. In five cats ventilatory responses to 5% CO2 were measured before and 5 min after 30 min of isocapnic hypoxia and before and after 30 min of room air breathing. Hypoxia did not affect CO2 responses. Thus the neurochemical events that cause hypoxic depression appear not to involve the neurons generating the response to CO2 and may be specific to those involved in the hypoxic response.