Background: Noninvasive ventilation (NIV) is an effective form of treatment in obesity hypoventilation syndrome (OHS) with severe obstructive sleep apnea (OSA). However, there is paucity of evidence in OHS patients without severe OSA phenotype. Research questions: Is NIV effective in OHS without severe OSA phenotype? Study design and methods: In this multicenter, open-label parallel group clinical trial performed at 16 sites in Spain, we randomly assigned 98 stable ambulatory patients with untreated OHS and apnea-hypopnea index <30 events/hour (i.e., no severe OSA) to NIV or lifestyle modification (control group) using simple randomization through an electronic database. The primary end point was hospitalization days/year. Secondary endpoints included other hospital resource utilization, incident cardiovascular events, mortality, respiratory functional tests, blood pressure, quality of life, sleepiness and other clinical symptoms. Both investigators and patients were aware of the treatment allocation; however, treating clinicians from the routine care team were not aware of patients' enrollment in the clinical trial. The study was stopped early in its 8th year due to difficulty identifying OHS patients without severe OSA. The analysis was performed according to intention-to-treat and per-protocol principles as well as by adherence subgroups. Results: 49 patients in the NIV group and 49 in the control group were randomized and 48 patients in each group were analyzed. During a median [IQR] follow-up of 4.98 [2.98; 6.62] years, mean (SD) hospitalization days/year was 2.60 (5.31) in the control group and 2.71 (4.52) in the NIV group [adjusted rate ratio (95% CI) 1.07 (0.44; 2.59) (p = 0.882)]. NIV therapy, in contrast to control group, produced significant longitudinal improvement in PaCO2, pH, bicarbonate, quality of life (SF-36 physical component) and daytime sleepiness. Moreover, per-protocol analysis showed statistically significant difference for the time until the first emergency department visit favoring NIV. In the subgroup with high NIV adherence the time until the first event of hospital admission, emergency department visits and mortality were longer than in the low adherence subgroup. Adverse events were similar between arms. Interpretation: In stable ambulatory patients with OHS without severe OSA, NIV and lifestyle modification had similar long-term hospitalization days-year. A more intensive program aimed at improving NIV adherence may lead to better outcomes. Larger studies are necessary to better determine the long-term benefit of NIV in this subgroup of OHS. Keywords: CPAP; noninvasive ventilation; obesity hypoventilation syndrome; sleep apnea.