The male predominance in obstructive sleep apnea (OSA) is currently poorly understood although differences in pharyngeal airway anatomy and physiology have been proposed. As the response to inspiratory resistive loading (IRL) provides important information on both airway collapsibility (mechanics) and ventilatory control, we compared this respiratory response in eight normal women and eight age and body mass index (BMI)-matched men, during stable nonrapid eye movement (NREM) sleep. Upper airway mechanics, ventilation, plus activation of two dilator muscles (genioglossus [GG] and tensor palatini [TP]) were monitored during basal breathing (BL), followed by four sequentially applied loads (5, 10, 15, 25 cm H(2)O/L/s) for three breaths each. Men developed more severe hypopnea in response to identical applied external loads than did women. At a resistance of 25 cm H(2)O/L/s, VT decreased by 26 +/- 1% in women compared with 44 +/- 1% in men (differences between sexes p < 0.05). Pharyngeal resistance (Rpha) in response to IRL increased significantly more in men than women (37.3 +/- 11.2 cm H(2)O/L/s in men at maximal load, compared with an increase of 6.6 +/- 3.9 cm H(2)O/L/s in women, p < 0.05). Men and women had near identical minute ventilation responses to total load (applied extrinsic plus measured intrinsic), implying no differences in central drive or load response. There were no significant increases in GG or TP activation in response to IRL in either sex. We conclude that normal men are more vulnerable to load-induced hypoventilation than women, due to increased upper airway collapse, which could not be explained by differences in dilator muscle activation. This implies a fundamental difference in the upper airway anatomy and/or tissue characteristics between the two sexes.