It is hypothesized that interleukin-1 (IL-1) is involved in physiological sleep. If this hypothesis is correct, inhibition of IL-1 should attenuate sleep responses after sleep deprivation. We tested the effect of intracerebroventricular or intravenous injection of an IL-1 inhibitor, an IL- 1 receptor fragment (IL-1RF), on sleep rebound after sleep deprivation in rabbits. Six hours of total sleep deprivation significantly increased non- rapid eye movement sleep (NREMS) and enhanced electroencephalogram slow-wave activity during NREMS. Intracerebroventricular treatment with the IL-1RF (50 μg) significantly attenuated the sleep responses after sleep deprivation. Furthermore, 1.0 mg/kg iv injection of the IL-1RF significantly suppressed spontaneous NREMS in rabbits that were not sleep deprived. However, intravenous administration of the IL-1RF (1.0 mg/kg) failed to attenuate the sleep responses following the 6-h sleep deprivation period. These results support the hypothesis that central pools of IL-1 are important for physiological sleep regulation.