In this issue of CHEST (see page 1678), Banerjee and colleagues16 provide new insights on the treatment of OHS. These investigators compared the impact of CPAP titration on the sleep architecture, respiratory events, and nocturnal hypoxemia in 23 patients with OHS and 23 patients with eucapnic OSA matched for BMI, apnea-hypopnea index (AHI), and lung function. Both groups were extremely obese with severe sleep-disordered breathing, and those with OHS had significant daytime hypercapnia. The protocol included full-night diagnostic polysomnography followed by a full night of CPAP titration without supplemental oxygen therapy, and CPAP was titrated to eliminate apneas, hypopneas, and any evidence of flow limitation. CPAP resolved sleep-disordered breathing and nocturnal hypoxemia in 57% of patients with OHS. The optimal CPAP pressure of 13.9 ± 3.1 cm H2O was reached within 1 h of sleep onset. CPAP was unable to resolve refractory hypoxemia in 43% of patients with OHS, and these patients had a higher BMI, more severe nocturnal hypoxemia at baseline, and a higher residual AHI during the night of CPAP titration compared to those with successful titration. Overall, CPAP led to significant increase in rapid eye movement sleep and significant reduction in arousal index and AHI in both patients with eucapnic OSA and OHS.