Introduction In people with obesity hypoventilation syndrome (OHS), breathing 100% oxygen increases carbon dioxide (PCO 2), but its effect on pH is unknown. This study investigated the effects of moderate concentrations of supplemental oxygen on PCO 2, pH, minute ventilation (VE) and physiological dead space to tidal volume ratio (VD/VT) among people with stable untreated OHS, with comparison to healthy controls. Methods In a double-blind randomised crossover study, participants breathed oxygen concentrations (F iO 2) 0.28 and 0.50, each for 20 min, separated by a 45 min washout period. Arterialised-venous PCO 2 (PavCO 2) and pH, VE and VD/VT were measured at baseline, then every 5 min. Data were analysed using general linear model analysis. Results 28 participants were recruited (14 OHS, 14 controls). Among OHS participants (mean±SD arterial PCO 2 6.7±0.5 kPa; arterial oxygen 8.9±1.4 kPa) F iO 2 0.28 and 0.50 maintained oxygen saturation 98-100%. After 20 min of F iO 2 0.28, PavCO 2 change (ΔPavCO 2) was 0.3±0.2 kPa (p=0.013), with minimal change in VE and rises in VD/VT of 1±5% (p=0.012). F iO 2 0.50 increased PavCO 2 by 0.5±0.4 kPa (p=0.012), induced acidaemia and increased VD/VT by 3±3% ( p=0.012). VE fell by 1.2±2.1 L/min within 5 min then recovered individually to varying degrees. A negative correlation between ΔVE and ΔPavCO 2 (r=-0.60, p=0.024) suggested that ventilatory responses were the key determinant of PavCO 2 rises. Among controls, F iO 2 0.28 and 0.50 did not change PavCO 2 or pH, but F iO 2 0.50 significantly increased VE and VD/VT. Conclusion Commonly used oxygen concentrations caused hypoventilation, PavCO 2 rises and acidaemia among people with stable OHS. This highlights the potential dangers of this common intervention in this group.