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Rationale: Obstructive sleep apnea (OSA) is an independent risk factor for stroke, but little is known about the role of continuous positive airway pressure (CPAP) on mortality in patients with stroke., Objectives: To analyze the independent impact of long-term CPAP treatment on mortality in patients with ischemic stroke., Methods: Prospective observational study in 166 patients with ischemic stroke. Sleep study was performed in all of them and CPAP treatment was offered in the case of moderate to severe cases. Patients were followed-up for 5 years to analyze the risk of mortality., Measurements and Main Results: Of 223 patients consecutively admitted for stroke, a sleep study was performed on 166 of them (2 mo after the acute event). Thirty-one had an apnea-hypopnea index (AHI) of less than 10; 39 had an AHI between 10 and 19, and 96 had an AHI of 20 or greater. CPAP treatment was offered when AHI was 20 or greater. Patients were followed up in our outpatient clinic at 1, 3, and 6 months, and for every 6 months thereafter for 5 years (prospective observational study). Mortality data were recorded from our computer database and official death certificates. The mean age of subjects was 73.3 +/- 11 years (59% males), and the mean AHI was 26 (for all patients with a predominance of obstructive events). Patients with an AHI of 20 or greater who did not tolerate CPAP (n = 68) showed an increase adjusted risk of mortality (hazards ratio [HR], 2.69; 95% confidence interval [CI], 1.32-5.61) compared with patients with an AHI of less than 20 (n = 70), and an increased adjusted risk of mortality (HR, 1.58; 95% CI, 1.01-2.49; P = 0.04) compared with patients with moderate to severe OSA who tolerated CPAP (n = 28). There were no differences in mortality among patients without OSA, patients with mild disease, and patients who tolerated CPAP., Conclusions: Our results suggest that long-term CPAP treatment in moderate to severe OSA and ischemic stroke is associated with a reduction in excess risk of mortality.