Abnormalities of ventilatory control may play a significant role in the pathophysiology of sleep-disordered breathing in patients with the Prader-Willi syndrome (PWS). We measured rebreathing hypercapnic and hypoxic ventilatory responses (HCVR and HPVR, respectively) during wakefulness in 8 nonobese PWS (NOB-PWS) and 9 obese PWS (OB-PWS) patients and compared their results with those from 24 healthy nonobese control (NOB-CON) and 10 obese control (OB-CON) subjects. The slope of HCVR was similar in NOB-PWS patients and NOB-CON subjects (NS). However, HCVR was significantly lower in OB-PWS patients than in OB-CON subjects (P < 0.02). In PWS patients, the mean point of origin of the positive slope of HCVR occurred at a significantly higher end-tidal PCO2 than in either control group. During isocapnic hypoxic challenges, six PWS patients had no significant HPVR. In the remainder, mean slopes of HPVR were -0.80 +/- 0.06 l.min-1.%arterial O2 saturation-1 in five NOB-PWS patients and -0.68 +/- 0.15 l.min-1.%arterial O2 saturation-1 in six OB-PWS patients. These responses were significantly decreased compared with those in the control groups (P < 0.006). We conclude that NOB-PWS patients have normal HCVR, which is blunted in OB-PWS patients. Furthermore, isocapnic HPVR is either absent or markedly reduced in PWS patients. The severity of abnormality of the HPVR is independent of the degree of obesity. We postulate that the primary abnormality of ventilatory control in PWS affects peripheral chemoreceptor pathways.