Tumor necrosis factor (TNF) is a well characterized sleep-regulatory substance. To study receptor mechanisms for the sleep-promoting effects of TNF, sleep patterns were determined in control and TNF 55 kDa receptor knock- out (TNFR-KO) mice with a B6 x 129 background after intraperitoneal injections of saline or murine TNFα. The TNFR-KO mice had significantly less baseline sleep than the controls. TNFα dose-dependently increased non-rapid eye movement sleep (NREMS) in the controls but did not influence sleep in TNFR-KO mice. Although TNFR-KO mice failed to respond to TNFα, they had an increase in NREMS and a decrease in rapid eye movement sleep after interleukin-1β treatment. These results indicate that TNFα affects sleep via the 55 kDa receptor and provide further evidence that TNFα is involved in physiological sleep regulation. Current results also extend the list of species to mice in which TNFα and interleukin-1β are somnogenic.