Background Current guidelines recommend that patients with obesity hypoventilation syndrome (OHS) are electively admitted for inpatient initiation of home non-invasive ventilation (NIV). We hypothesised that outpatient NIV setup would be more cost-effective. Methods Patients with stable OHS referred to six participating European centres for home NIV setup were recruited to an open-labelled clinical trial. Patients were randomised via web-based system using stratification to inpatient setup, with standard fixed level NIV and titrated during an attended overnight respiratory study or outpatient setup using an autotitrating NIV device and a set protocol, including home oximetry. The primary outcome was cost-effectiveness at 3 months with daytime carbon dioxide (PaCO 2 ) as a non-inferiority safety outcome; non-inferiority margin 0.5 kPa. Data were analysed on an intention-to-treat basis. Health-related quality of life (HRQL) was measured using EQ-5D-5L (5 level EQ-5D tool) and costs were converted using purchasing power parities to £(GBP). Results Between May 2015 and March 2018, 82 patients were randomised. Age 59±14 years, body mass index 47±10 kg/m 2 and PaCO 2 6.8±0.6 kPa. Safety analysis demonstrated no difference in ∆PaCO 2 (difference −0.27 kPa, 95% CI −0.70 to 0.17 kPa). Efficacy analysis showed similar total per-patient costs (inpatient £2962±£580, outpatient £3169±£525; difference £188.20, 95% CI −£61.61 to £438.01) and similar improvement in HRQL (EQ-5D-5L difference −0.006, 95% CI −0.05 to 0.04). There were no differences in secondary outcomes. Discussion There was no difference in medium-term cost-effectiveness, with similar clinical effectiveness, between outpatient and inpatient NIV setup. The home NIV setup strategy can be led by local resource demand and patient and clinician preference. Trial registration numbers NCT02342899 and ISRCTN51420481 .