Mechanisms for the control of episodic fetal breathing movements or the onset of continuous breathing at birth remain unknown. Lung distension with 100% O2at a continuous positive airway pressure of 30 cm H2O may induce arousal and continuous breathing. To investigate1) the threshold range of arterial oxygen tension (PaO2) for the onset of arousal and breathing and2) the graded response of breathing to various levels of PaO2, we studied 10 fetal sheep between 135 and 142 d of gestation (term = 147 ± 2 d). Each fetus was instrumented to record sleep states, diaphragmatic electromyogram, arterial pH, and blood gas tensions. PaO2threshold was determined through an indwelling O2sensor catheter. Fetal lungs were distended at a continuous positive airway pressure of 40 cm H2O with 100%. N2or with O2ranging from 40 to 100% via an in situ endotracheal tube. At the onset of arousal (n= 10), PaO2, arterial carbon dioxide tension, and Hb O2saturation increased from control values of 21.7 ± 0.75 torr (2.9 ± 0.09 kPa), 41.8 ± 1.1 torr (5.47 ± 0.15 kPa), and 52.9 ± 2.6% to 65.6 ± 9.6 torr (8.74 ± 1.28 kPa), 46.9 ±1.3 torr (6.25 ± 0.17 kPa), and 92.9 ± 2.06%, respectively, whereas the pH decreased from 7.31 ± 0.006 to 7.27 ± 0.009 (mean ± SEM; p = 0.001, 0.04, 0.002, and 0.001, respectively). Seven of 10 fetuses breathed continuously. In these fetuses, PaO2and arterial carbon dioxide tension further increased and pH decreased; however, no further significant increase in Hb O2saturation was observed. Breathing stopped at a PaO2of 38.5 ± 9.5 torr (5.1 ±1.3 kPa) but could be restarted by increasing the PaO2. In response to an increase in fetal PaO2(30–60 torr; 4–8 kPa), amplitude of breathing and total respiratory output significantly increased from the control values. Further increases in PaO2or Hb O2saturation did not significantly affect the respiratory output. Hb O2saturation and arterial pH had the most confounding effects on frequency and amplitude of breathing, respectively. Among the various sleep states, arousal had the most profound effects on respiratory output. We conclude that 1) very high levels of PaO2are not necessary to initiate arousal and continuous breathing and2) further increments in Hb O2saturation above the threshold level have no significant effect on breathing responses. (Pediatr Res 32: 342–349, 1992)