The involvement of tumor necrosis factor (TNF) in sleep regulation was investigated by blocking TNF using a synthetic TNF receptor fragment (TNFRF) in rabbits. Intracerebroventricular injection of 50 μg TNFRF decreased spontaneous non-rapid-eye-movement (NREM) sleep across the 21 h recording period. After 6 h of sleep deprivation (SD), both duration of NREM sleep and electroencephalographic (EEG) slow wave activity during NREM sleep were enhanced. TNFRF suppressed SD-enhanced NREM sleep and EEG slow wave activity. SD per se did not affect rapid-eye-movement (REM) sleep, but TNFRF treatment increased REM sleep after SD. These results are consistent with the hypothesis that TNF is involved in the regulation of physiological NREM sleep.