Background:The key determinants of daytime drowsiness in sleep disordered breathing (SDB) are unclear. Hypercapnia has not been examined as a potential contributor due to the lack of reliable measurement during sleep. To overcome this limitation, we studied predominantly hypercapnic SDB patients to investigate the role of hypercapnia on EEG activation and daytime sleepiness. Methods: We measured overnight polysomnography (PSG), arterial blood gases, and Epworth Sleepiness Scale in 55 severe SDB patients with obesity hypoventilation syndrome or overlap syndrome (COPD+ obstructive sleep apnea) before and ~3 months after positive airway pressure (PAP) treatment. Quantitative EEG analyses were performed, and the Delta/ Alpha ratio was used as an indicator of EEG activation. Results: After the PAP treatment, these patients showed a signifi cant decrease in their waking pCO 2 , daytime sleepiness, as well as all key breathing/oxygenation parameters during sleep. Overnight Delta/Alpha ratio of EEG was signifi cantly reduced. There is a signifi cant cross-correlation between a reduced wake pCO 2 , a faster (more activated) sleep EEG (reduced Delta/Alpha ratio) and reduced daytime sleepiness (all p < 0.05) with PAP treatment. Multiple regression analyses showed the degree of change in hypercapnia to be the only signifi cant predictor for both ESS and Delta/ Alpha ratio. Conclusions: Hypercapnia is a key correlate of EEG activation and daytime sleepiness in hypercapnic SDB patients. The relationship between hypercapnia and sleepiness may be mediated by reduced neuro-electrical brain activity.