Sleep is essential to maintaining health and well-being. It has been demonstrated that some of the biological alterations caused by paradoxical sleep deprivation (PSD) are not completely reversed after a period of sleep rebound (SR). The purpose of this study was to determine to what extent the specific molecular changes that occur in the rat cerebral cortex after 96 h of PSD can effectively be reversed during 24h of recovery. Total RNA from the right cerebral cortex of Wistar male rats and GeneChip Rat Genome 230 2.0 arrays were used to perform comprehensive microarray analysis of gene expression in control, PSD and SR groups. Microarray data were validated by Real Time qPCR. A total of 78 unique transcripts were differently expressed after PSD relative to control levels. These include genes related to metabolic processes, the circadian sleep-wake cycle, response to stimuli, regulation of cell proliferation and signaling pathways. After 24h of sleep rebound, approximately 62% of the sleep deprivation transcripts were again detected as differently expressed in the SR relative to the PSD group, although in the opposite direction. On the other hand, the expression of the remaining transcripts showed intermediate values between control and sleep-deprived animals. In summary, our results provide a unique set of transcripts that might be specific related to regulation of paradoxical sleep phase and sleep homeostasis processes, as well as to the biological basis of sleep disorders.