Orexin-A is a neuropeptide involved in the regulation of food intake and the sleep-wake cycle. This study investigated plasma orexin-A levels in a sleep clinic cohort, adjusting for smoking habits, in 76 participants comprising 41 with obstructive sleep apnoea (OSA) (apnoea-hypopnoea index [AHI] 44.1 +/- 19.1 events/h) and 35 without OSA (AHI 6.3 +/- 4.7 events/h). Plasma orexin-A levels were significantly lower in OSA patients (15.0 +/- 4.6 ng/ml) compared with those without OSA (31.4 +/- 6.5 ng/ml). In non-OSA subjects, there was no significant difference between never smokers and ex/current smokers in plasma orexin-A levels (32.9 +/- 9.5 versus 29.7 +/- 8.9 ng/ml, respectively) whereas, in the OSA sub-group, orexin-A levels were significantly lower in never smokers than in ex/current smokers (4.0 +/- 1.2 versus 21.4 +/- 7.0 ng/ml). A significant inverse relationship was found between plasma orexin-A levels and AHI amongst never smokers, but there was no significant relationship amongst ex/current smokers. These results confirm previous studies demonstrating lower levels of plasma orexin-A in OSA patients and indicate that smoking may affect orexin-A levels and AHI.