We hypothesize that sleep homeostasis involves, at least in part, the immune system modulator interleukin-1 beta (IL-1 beta). Using the reverse transcription-polymerase chain reaction, IL-1 beta mRNA levels in the rat CNS were evaluated after a period of sleep deprivation. In addition, IL-1 beta gene expression was analyzed before the projected onset of activity and rest phase in free-running animals. No changes in IL-1 beta mRNA were observed in the circadian cycle, but 24 h of sleep deprivation resulted in a 2-fold increase in the level of IL-1 beta mRNA in the hypothalamus and in the brain stem compared with controls (p < 0.0002 and (p < 0.0001 respectively). The alteration in IL-1 beta mRNA levels following sleep deprivation supports the hypothesis that modulation of IL-1 beta gene expression is involved in the sleep homeostatic process.