The dimeric transcription factor nuclear factor-kappa B (NF-B) regulates several endogenous sleep-modulatory substances, and thereby serves as a pivotal mediator of sleep-wake regulation. To further define the role of NF-B in sleep regulation, we monitored sleep and temperature in mice that lack the p50 subunit of NF-B (p50 KO mice). As compared to the control B6129PF2/J strain, p50 KO mice spend more time in slow wave sleep (SWS) and rapid eye movement sleep (REMS) under normal conditions and show enhanced homeostatic recovery of sleep after sleep loss. p50 KO mice also show increased SWS and reduced REMS and temperature after the administration of lipopolysaccharide, yet they are behaviorally less responsive to challenge with influenza virus. These data support a role for NF-B, and, in particular, for the p50 subunit, in the regulation of sleep in healthy mice and in mice experiencing immune challenge.