Open studies suggest that treatment of obesity hypoventilation syndrome (OHS) by noninvasive ventilation (NIV) restores sleep quality and daytime vigilance and reduces cardiovascular morbidity. However, to our knowledge no randomized controlled trial (RCT) comparing NIV to conservative measures is available in the field. The goal of this study was to assess in patients with OHS, during an RCT, effects of 1-month NIV compared with lifestyle counseling on blood gas measurements, sleep quality, vigilance, and cardiovascular, metabolic, and inflammatory parameters. Thirty-five patients in whom OHS was newly diagnosed were randomized either to the NIV group or the control group represented by lifestyle counseling. Assessments included blood gas levels, subjective daytime sleepiness, metabolic parameters, inflammatory (hsCRP, leptin, regulated upon activation normal T-cell express and secreted [RANTES], monocyte chemoattractant protein-1, IL-6, IL-8, tumor necrosis factor-α, resistin) and antiinflammatory (adiponectin, IL-1-RA) cytokines, sleep studies, endothelial function (reactive hyperemia measured by peripheral arterial tonometry [RH-PAT]), and arterial stiffness. Despite randomization, NIV group patients (n = 18) were older (58 ± 11 years vs 54 ± 6 years) with a higher baseline Paco(2) (47.9 ± 4.2 mm Hg vs 45.2 ± 3 mm Hg). In intention-to-treat analysis, compared with control group, NIV treatment significantly reduced daytime Paco(2) (difference between treatments: -3.5 mm Hg; 95% CI, -6.2 to -0.8) and apnea-hypopnea index (-40.3/h; 95% CI, -62.4 to -18.2). Sleep architecture was restored, although nonrespiratory microarousals increased (+9.4/h of sleep; 95% CI, 1.9-16.9), and daytime sleepiness was not completely normalized. Despite a dramatic improvement in sleep hypoxemia, glucidic and lipidic metabolism parameters as well as cytokine profiles did not vary significantly. Accordingly, neither RH-PAT (+0.02; 95% CI, -0.24 to 0.29) nor arterial stiffness (+0.22 m/s; 95% CI, -1.47 to 1.92) improved. One month of NIV treatment, although improving sleep and blood gas measurements dramatically, did not change inflammatory, metabolic, and cardiovascular markers. ClinicalTrials.gov; No.: NCT00603096; URL: www.clinicaltrials.gov.