Obesity-hypoventilation syndrome (OHS) is a respiratory complication of obesity characterized by chronic hypercapnic respiratory failure. It is often associated with several comorbidities and is treated by positive airway pressure (PAP) therapy. This study aimed to identify factors associated with persistent hypercapnia in patients receiving home non-invasive ventilation (NIV). We performed a retrospective study including patients with documented OHS. In total, 143 patients were included (79.7% women, age 67 ± 15.5 years, body mass index 41.6 ± 8.3 kg/m2). After 4.6 ± 4.0 years of follow-up, 72 patients (50.3%) remained hypercapnic. In bivariable analysis, clinical data showed no difference in follow-up duration, number of comorbidities, comorbidities, or circumstance of discovery. Patients with persistent hypercapnia on NIV were generally older, with lower BMI and more comorbidities. (5.5 ± 1.8 versus 4.4 ± 2.1,p= 0.001), female sex (87.5% versus 71.8%), was treated by NIV (100% versus 90.1%,p< 0.01), had lower FVC (56.7 ± 17.2 versus 63.6 ± 18% of theoretical value,p= 0.04), lower TLC (69.1 ± 15.3 versus 74.5 ± 14.6% of theoretical value,p= 0.07), lower RV (88.4 ± 27.1 versus 102.5 ± 29.4% of theoretical value,p= 0.02), higher pCO2 at diagnosis (59.7 ± 11.7 versus 54.6 ± 10.1 mmHg,p= 0.01) and lower pH (7.38 ± 0.03 versus 7.40 ± 0.04,p= 0.007), higher pressure support (12.6 ± 2.6 versus 11.5 ± 2.4 cmH2O,p= 0.04) and lower EPAP (8.2 ± 1.9 versus 9 ± 2.0 cmH2O,p= 0.06). There was no difference in non-intentional leaks and daily use between patients between both groups. By multivariable analysis, sex, BMI, pCO2 at diagnosis, and TLC were independent risk factors for persistent hypercapnia on home NIV. In individuals with OHS, persistent hypercapnia on home NIV therapy is frequent. Sex, BMI, pCO2 at diagnosis, and TLC were all associated with an increased risk of persistent hypercapnia in persons treated with home NIV.