Proinflammatory cytokines, including interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha, are involved in sleep regulation. IL-4 is an antiinflammatory cytokine that inhibits proinflammatory cytokine production. The hypothesis that IL-4 should attenuate sleep was studied by determining the effects of IL-4 on rabbit spontaneous sleep. Thirty-six rabbits were used. Four doses of IL-4 (0.25, 2.5, 25, and 250 ng) were injected intracerebroventricularly during the rest (light) period. One dose of IL-4 (25 ng) was injected during the active (dark) cycle. Appropriate time-matched control injections of saline were done in the same rabbits on different days. The three highest doses of IL-4 significantly inhibited spontaneous non-rapid eye movement sleep if IL-4 was given during the light cycle. The highest dose of IL-4 (250 ng) also significantly decreased rapid eye movement sleep. On the other hand, IL-4 administered at dark onset had no effect on sleep. The sleep inhibitory properties of IL-4 provide additional evidence for the hypothesis that a brain cytokine network is involved in the regulation of physiological sleep.