Recent studies suggest that narcolepsy is caused by degeneration of hypocretin (orexin) producing neurons. To find evidence for this hypothesis, we aimed to detect structural changes in the hypothalamus and/or hypocretin projection areas of patients with narcolepsy.We used voxel-based morphometry (VBM), an unbiased MRI morphometric method with a high sensitivity for subtle changes in gray and white matter volumes.Image acquisition was carried out in the department of Radiology at Leiden University Medical Center; image post-processing was performed in the Wellcome Department of Cognitive Neurology, London.Fifteen narcoleptic patients were studied, all having cataplexy and typical findings on Multiple Sleep Latency Testing. All patients were HLA-DQB1*0602 positive and hypocretin-1 deficient. The control group consisted of 15 age and sex matched healthy subjects.We found no differences in global gray or white matter volumes between patients and controls. Furthermore, regional gray or white matter volumes in the hypothalamus and hypocretin projection areas did not differ between patients and controls.VBM failed to show structural changes in the brains of patients with narcolepsy. This suggests that narcolepsy either is associated with microscopic changes undetectable by VBM or that functional abnormalities of hypocretin neurons are not associated with structural correlates.