Summary Hypoxic brain damage might explain persistent sleepiness in some continuous positive airway pressure‐compliant obstructive sleep apnea called residual excessive sleepiness. Although continuous positive airway pressure may not be fully efficient in treating this symptom, wake‐promoting drug prescription in residual excessive sleepiness is no longer allowed by the European Medicines Agency. The aim of this study is to describe residual excessive sleepiness phenotypes in a large prospective sample of patients with obstructive sleep apnea. Residual excessive sleepiness was defined by an Epworth Sleepiness Scale score ≥ 11. Eligible patients from the French National Sleep Registry attending follow‐up continuous positive airway pressure visits numbered 1047. Patients using continuous positive airway pressure < 3 h (n = 275), with residual apnea–hypopnea index > 15 h−1 (n = 31) or with major depression were excluded (n = 150). Residual excessive sleepiness prevalence in continuous positive airway pressure‐treated obstructive sleep apnea was 13% (18% for those with an initial Epworth Sleepiness Scale score > 11), and significantly decreased with continuous positive airway pressure use (9% in ≥ 6 h night−1 continuous positive airway pressure users, P < 0.005). At the time of diagnosis, patients with residual excessive sleepiness had worse subjective appreciation of their disease (general health scale, Epworth Sleepiness Scale and fatigue score), and complained more frequently of continuous positive airway pressure side‐effects. Residual excessive sleepiness prevalence was lower in severe obstructive sleep apnea than in moderate obstructive sleep apnea (11% when AHI > 30 h−1 versus 18% when AHI 15–30, P < 0.005). There was no relationship between residual excessive sleepiness and body mass index, cardiovascular co‐morbidities or diabetes. Continuous positive airway pressure improved symptoms in the whole population, but to a lower extent in patients with residual excessive sleepiness (fatigue scale: −5.2 versus −2.7 in residual excessive sleepiness− and residual excessive sleepiness+ patients, respectively, P < 0.001). Residual excessive sleepiness prevalence decreased with continuous positive airway pressure compliance. Hypoxic insult is unlikely to explain residual excessive sleepiness as obstructive sleep apnea severity does not seem to be critical. Residual symptoms are not limited to sleepiness, suggesting a true ‘continuous positive airway pressure‐resistant syndrome’, which may justify treatment by wake‐promoting drugs.

NCT 01029561.