The role of ventilatory-control abnormalities in predisposing to familial sleep-disordered breathing (SDB) was assessed in 31 subjects 28 +/- 10 yr of age (mean +/- SD). Subjects with (n = 10) and without SDB (n = 12) were recruited from 13 families having two or more members with SDB. Nine age- and gender-matched controls were recruited from families having no member with SDB. Respiratory responses to eucapnic hypoxia, and ventilatory and occlusion pressure responses to hyperoxic hypercapnia with and without added resistive loads (6.5 cm H2O/L/s), were assessed through rebreathing. Age, FEV1, and FVC did not differ among the groups. Hypoxic responses (delta VE/delta SaO2) were significantly lower among the first-degree relatives of SDB families than among controls (-0.76 +/- 0.47 L/min/% SaO2, and -1.32 +/- 0.92 L/min/% SaO2, respectively, p < 0.05). Respiratory responses to hypercapnia during unloaded conditions were similar among the groups. With resistive loading, inspiratory impedance, as measured through the relationship of mouth occlusion pressure (P100) to inspiratory flow (VT/TI), increased with increasing hypercapnia to a greater extent in members of SDB families than in controls (0.169 +/- 0.054 cm H2O/L/min versus 0.122 +/- 0.051, respectively, p < 0.05). These data suggest that familial SDB may be based partly on a familial abnormality in ventilatory control associated with blunting of the hypoxic ventilatory response. The greater increase in impedance during inspiratory loading in members of affected families also suggests a propensity for dynamic airway narrowing.