Obstructive sleep apnea (OSA) resolves in lateral sleep in 20 of patients. However, the effect of lateral positioning on factors contributing to OSA has not been studied. We aimed to measure the effect of lateral positioning on the key pathophysiological contributors to OSA including lung volume, passive airway anatomy/collapsibility, the ability of the airway to stiffen and dilate, ventilatory control instability (loop gain), and arousal threshold. DESIGN: Non-randomized single arm observational study. SETTING: Sleep laboratory. PATIENTS/PARTICIPANTS: 20 (15M, 5F) continuous positive airway pressure (CPAP)-treated severe OSA patients. INTERVENTIONS: Supine vs. lateral position. MEASUREMENTS: CPAP dial-downs performed during sleep to measure: (i) Veupnea: asleep ventilatory requirement, (ii) passive V0: ventilation off CPAP when airway dilator muscles are quiescent, (iii) Varousal: ventilation at which respiratory arousals occur, (iv) active V0: ventilation off CPAP when airway dilator muscles are activated during sleep, (v) loop gain: the ratio of the ventilatory drive response to a disturbance in ventilation, (vi) arousal threshold: level of ventilatory drive which leads to arousal, (vii) upper airway gain (UAG): ability of airway muscles to restore ventilation in response to increases in ventilatory drive, and (viii) pharyngeal critical closing pressure (Pcrit). Awake functional residual capacity (FRC) was also recorded. RESULTS: Lateral positioning significantly increased passive V0 (0.33 +/- 0.76L/min vs. 3.56 +/- 2.94L/min, P <0.001), active V0 (1.10 +/- 1.97L/min vs. 4.71 +/- 3.08L/min, P <0.001), and FRC (1.31 +/- 0.56 L vs. 1.42 +/- 0.62 L, P = 0.046), and significantly decreased Pcrit (2.02 +/- 2.55 cm H2O vs. -1.92 +/- 3.87 cm H2O, P <0.001). Loop gain, arousal threshold, Varousal, and UAG were not significantly altered. CONCLUSIONS: Lateral positioning significantly improves passive airway anatomy/collapsibility (passive V0, pharyngeal critical closing pressure), the ability of the airway to stiffen and dilate (active V0), and the awake functional residual capacity without improving loop gain or arousal threshold.