Adenosine (ADO) receptor antagonists (aminophylline, caffeine) blunt the respiratory roll-off response to hypoxia in the newborn. This study was designed to determine the ADO receptor subtype involved in the respiratory depression. Chronically catheterized lambs of 7-16 days of age breathed via facemask a gas mixture with a fraction of inspired O₂ of 0.21 (normoxia) or 0.07 (hypoxia) while being infused intravascularly with DPCPX (ADO A₁ receptor antagonist, n = 8), ZM-241385 (ADO A_2A receptor antagonist, n = 7), or vehicle. Ventilation was measured at 20°C by a turbine transducer flowmeter. In normoxia (PaO₂ ~ 83 Torr), infusion of vehicle did not alter cardiorespiratory measurements, while hypoxia (PaO₂ ~ 31 Torr, 15 min) elicited biphasic effects on mean arterial pressure (transient increase), heart rate (diminishing tachycardia), and minute ventilation. In the latter, hypoxia increased ventilation to a peak value of ~2.5 times control within the first 3 min, which was followed by a significant (P < 0.05) decline to ~50% of the maximum increment over the subsequent 7 min. ZM-241385 abolished the hypoxic ventilatory roll-off and blunted the rate of rise in HR without affecting MAP or rectal temperature responses. In normoxia, DPCPX increased ventilation and MAP but did not change HR. Compared to vehicle, DPCPX did not significantly affect cardiorespiratory responses to hypoxemia (PaO₂ ~ 31 Torr, 10 min). It is concluded that: 1) ADO A_2A receptors are critically involved in the ventilatory roll-off and HR responses to hypoxia, and 2) ADO A₁ receptors, which are tonically active in cardiorespiratory control in normoxia, appear to have little impact on hypoxic ventilatory depression.