Objective: Orexins are neuropeptides that are expressed in the lateral hypothalamus and involved in regulation of the arousal states. The sleep disorder narcolepsy, which is characterized by excessive daytime sleepiness and occurrence of sudden rapid eye movement sleep, is associated with a loss of orexin neurons. Our study investigated the effects of orexins on sleep-wake patterns in a novel transgenic mouse line overexpressing the human prepro-orexin (hPPO) gene under the control of its endogenous promoter. Methods: Orexin overexpression was investigated by PCR, Southern- and Western blotting as well as immunohistochemistry. Polysomnographic recordings were performed for analyses of sleep/wake patterns and for electroencephalographic activity during 24 hour baseline and during and after 6 hours of sleep deprivation. Results: Transgenic hPPO mice had increased expression of human prepro-orexin and orexin-A in the hypothalamus. Transgene expression decreased endogenous orexin-2 receptors but not orexin-1 receptors in the hypothalamus without affecting orexin receptors levels in the basal forebrain, cortex or hippocampus. Transgenic mice as compared to their wild type littermates showed significant differences in the amount of waking and slow wave sleep, particularly during the light-dark transition periods, in addition to a slight reduction of rapid eye movement sleep during baseline and during recovery sleep after sleep deprivation. Conclusion: The hPPO overexpressing mice show a small reduction of rapid eye movement sleep, in addition to differences in vigilance state amounts in the light/dark transition periods, but overall the sleep-wake patterns of hPPO overexpressing mice do not significantly differ from their wildtype littermates. Supported in part by the Academy of Finland.