The functions of rapid eye movement (REM) sleep have remained elusive since more than 50 years. Previous reports have identified several independent processes affected by the loss and subsequent recovery of REM sleep (hippocampal neurogenesis, brain stem neuronal cell death, and neurotransmitter content in several brain regions); however, a common underlying mechanism has not been found. We propose that altered brain homeostasis secondary to blood-brain barrier breakdown may explain all those changes induced by REM sleep loss. Therefore, the present report aimed to study the consequences of REM sleep restriction upon blood-brain barrier permeability to Evans blue. REM sleep restriction was induced by the multiple platform technique; male rats were REM sleep restricted 20h daily (with 4h sleep opportunity) during 10 days; control groups included large platform and intact rats. To study blood-brain barrier permeability Evans blue was intracardially administered; stained brains were sliced and photographed for optical density quantification. An independent experiment was carried out to elucidate the mechanism of blood-brain breakdown by transmission electron microscopy. REM sleep restriction increased blood-brain barrier permeability to Evans blue in the whole brain as compared to both control groups. Brief periods of sleep recovery rapidly and effectively restored the severe alteration of blood-brain barrier function by reducing blood-to-brain transfer of Evans blue. The mechanism of bloodbrain barrier breakdown involved increased caveolae formation at brain endothelial cells. In conclusion, our data suggest that REM sleep regulates the physical barrier properties of the blood-brain barrier.