Objective: Orexins are hypothalamic neuropeptides that are involved in feeding, neuroendocrine regulation, sleep-wakefulness and sleep disorders (such as narcolepsy). This study investigated the relationship between serum and cerebrospinal fluid (CSF) orexin-A concentrations and infarct volume, in patients with ischaemic stroke. Methods: Serum and CSF concentrations of orexin-A were determined 48-72 h after the onset of ischaemic stroke in patients, then compared with those of healthy control subjects of comparable age. Infarct volumes were measured using computerized tomography, 48-72 h after hospitalization. Results: Mean serum and CSF orexin-A concentrations were significantly lower among ischaemic stroke patients (n1/429) compared with control subjects (n1/413). There was a significant inverse correlation between infarct volumes and CSF orexin-A concentrations in patients with ischaemic stroke. Conclusion: These data show that serum and CSF orexin-A concentrations decrease after cerebral ischaemia and may play a role in the development of brain injury. The orexin-A concentration in the CSF might be a useful biomarker for the assessment of progression of brain tissue damage during the early stages of ischaemic stroke. © The Author(s) 2013.