events in obstructive sleep apnea (OSA) patients, potentially contributing to the disorder's severity. As acetazolamide can reduce apnea severity in some patients, we examined the effect of acetazolamide on the ventilatory response to spontaneous arousals in CPAP-treated OSA patients. Design: We assessed the ventilatory response to arousal in OSA patients on therapeutic CPAP before and after administration of acetazolamide for 7 days. Setting: Sleep research laboratory. Participants: 12 (7M/5F) CPAP-treated OSA patients. Interventions: Sustained-release acetazolamide 500 mg by mouth twice daily for one week. Measurements and Results: A blinded investigator identified spontaneous arousals (3-15 s) during NREM sleep. Breath-by-breath measurements of minute ventilation, end-tidal CO2, tidal volume, expiratory/inspiratory-time, and total breath duration were determined (4-s intervals) 32 s prior and 60 s following each arousal. Acetazolamide significantly increased resting ventilation (7.3 ± 0.2 L/min versus 8.2 ± 0.4 L/min; P < 0.05) and attenuated the percent increase in ventilation following arousal by ̃2.5 fold (122.0% ± 4.4% versus 108.7% ± 3.5% pre-arousal level; P < 0.05). There was a positive correlation between the mean increase in ventilatory response to arousal and mean AHI (r2 = 0.44, P = 0.01). However, absolute peak levels of ventilation following arousal remained unchanged between conditions (8.8 ± 0.4 L/min versus 8.9 ± 0.1 L/min). Conclusions: Acetazolamide substantially attenuates the increase in ventilation following spontaneous arousal from sleep in OSA patients. This study suggests an additional mechanism by which acetazolamide may contribute to the improvement in ventilatory instability and OSA severity. The data also provide support for reinforcing the importance of ventilatory control in OSA pathogenesis.