In response to infectious stimuli, enhanced non-rapid eye movement sleep (NREMS) occurs, which is driven by pro-inflammatory cytokines. Those cytokines further elicit the release of corticotropin-releasing hormone (CRH), resulting in the activation of the hypothalamic-pituitary-adrenocortical axis. Signals of CRH are mediated by two receptor types, namely CRH-R1 and -R2. The role of CRH-R1 in wake-promoting effects of CRH has been rather clarified, whereas the involvement of CRH-R2 in sleep-wake regulation is poorly understood. To investigate whether CRH-R2 interferes with sleep responses to immune challenge, this study examined effects of bacterial lipopolysaccharide (LPS) on sleep in CRH-R2 deficient (KO) mice. CRH-R2 KO mice and control littermates (CL) were implanted with electrodes for recording electroencephalogram (EEG) and electromyogram. After recovery, LPS was applied by intraperitoneal injection at doses of 0.1, 1.0, or 10 μg at dark onset. In response to LPS injection NREMS of both genotypes was enhanced in a dose-dependent manner. However, CRH-R2 KO mice showed a larger increase, in particular after 10 μg of LPS compared to CL mice. During postinjection, reduced delta power for NREMS was detected in both genotypes after each dose, but the highest dose evoked a marked elevation of EEG activity in a limited frequency band (4 Hz). However, the EEG power of lower frequencies (1-2 Hz) increased more in CRH-R2 KO than in CL mice. The results indicated that CRH-R2 KO mice show greater NREMS responses to LPS, providing evidence that CRH-R2 participates in sleep-wake regulation via an interaction with the activated immune system.