In an attempt to determine whether PO2 or O2 saturation is stimulus for the hypoxic ventilatory drive, we studied 2 brothers with the high O2 affinity hemoglobin Ranier (P50 approximately equal to 12 mm Hg). The ventilatory response to PO2 was normal. The O2 saturation did decrease slightly, and the ventilatory response to the decrease in O2 saturation was greatly exaggerated. We conclude that these findings are consistent with either of 2 possibilities: (1) that PO2 provides the stimulus to the hypoxic ventilatory response, or (2) that patients with high-affinity hemoglobin have increased sensitivity to arterial O2 desaturation.