We tested the hypothesis that continuous positive airway pressure (CPAP) use and outcomes can be improved by an autotitrating CPAP device in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) who require higher CPAP (10 cm H2O or more). In this multisite randomized single-blind cross-over study, 44 patients (mean age, 49 +/- 10 years) were randomized to 6 weeks at laboratory-determined fixed pressure and 6 weeks on autotitrating CPAP. Average nightly use was greater in automatic mode (306 versus 271 minutes, p = 0.005); median and 95th centile pressures in automatic mode were lower (p < 0.002). Automatic CPAP resulted in better SF-36 Vitality scores (65 +/- 20 versus 58 +/- 23, p < 0.05) and mental health scores (80 +/- 14 versus 75 +/- 18, p < 0.05), but no significant difference in Epworth score (p = 0.065). During automatic therapy, patients reported more restful sleep, better quality sleep, less discomfort from pressure, and less trouble getting to sleep for both the first week of therapy and for the averaged scores for Weeks 2-6 (all p values < 0.006). Patients who require higher fixed CPAP use autotitrating CPAP more and report greater benefit from this therapy.