We hypothesised that hypocretin (orexin) plays a role in the determination of ventilatory chemosensitivity. 130 patients with narcolepsy-cataplexy (mean±SD age 20±10 yrs, 69% male) and 117 controls (22±6.9 yrs, 62% male) were recruited and tested for human leukocyte antigen (HLA)-DQB1*0602 status, hyperoxia hypercapnic (change in minute ventilation (ΔV′E)/carbon dioxide tension (ΔPCO2) L·min-1·mmHg-1) and hypoxic (ΔV′E /change in arterial oxygen saturation measured by probe oximetry (ΔSp,O2) L·min-1 per %Sp,O 2) responsiveness, and by spirometry. Hypocretin deficiency was determined either by measures of cerebrospinal fluid hypocretin-1 (37 patients) or by positive HLA-DQB1*0602 status. All patients and 49% of controls underwent polysomnography and multiple sleep latency testing. Despite similar spirometric values, patients had a higher apnoea/hypopnoea index (AHI) (2.8±5.4 versus 0.8±1.6 h-1; p=0.03) and lower minimal oxygen saturation during sleep (87%±7 versus 91±4%; p=0.0002), independent of age, sex and body mass index. Patients had depressed hypoxic responsiveness (0.13±0.09 versus 0.19±0.13 L·min -1 per %Sp,O2; p<0.0001), independent of AHI, but hypercapnic responsiveness did not differ. Examined by HLA status, positive (26 out of 117) controls had lower hypoxic but similar hypercapnic responsiveness than those marker-negative (0.13±0.08 versus 0.20±0.14 L·min-1 per %Sp,O2; p<0.0001). Thus, a lower hypoxic responsiveness in the narcolepsy-cataplexy group is a result of DQB1*0602 status rather than the clinical features of disease. Copyright©ERS 2010.