Interleukin (IL)-1 and tumor necrosis factor (TNF) are involved in the regulation of non-rapid eye movements sleep (NREMS). Accumulating evidence suggests IL-6 modulates sleep under some pathophysiologic conditions. We used mice lacking a functional IL-6 gene to investigate further a potential role for IL-6 in the regulation of sleep. IL-6 knockout mice (B6.129S6-Il6tm1Kopf; n=10) and C57BL/6J mice (n=10) were purchased from the Jackson Laboratory (Bar Harbor, ME). Twenty-four-hour baseline recordings were obtained from mice in the absence of any experimental manipulation. Mice were then subjected to 6-h sleep deprivation beginning at light onset. Recordings were obtained during the deprivation period and for 18 h thereafter. During baseline conditions there were no differences between mouse strains with respect to the duration, timing or intensity of NREMS. However, across the 24-h recording period IL-6 knockout mice spent approximately 30% more time in rapid eye movements sleep (REMS) than did C57BL/6J mice. Relative to C57BL/6J mice, core body temperatures of IL-6 knockout mice were higher during the light period of the light:dark cycle. Both strains responded to sleep deprivation by spending more time in NREMS and REMS. Although the total increase in the amount of NREMS after sleep deprivation was the same in both strains, IL-6 knockout mice took 6h longer to accumulate this additional sleep. Under the conditions of this study, IL-6 does not appear necessary for the full manifestation of NREMS, although this cytokine may influence the dynamics of responses to sleep deprivation. That mice lacking IL-6 spend more time in REMS suggests that interactions between IL-6 and REMS regulatory mechanisms may differ from those of IL-1 and/or TNF.