OBJECTIVES: Delirium occurs in approximately 30% of critically ill patients, and the risk of dying during admission doubles in those patients. Molecular mechanisms causing delirium are largely unknown. However, critical illness and the ICU environment consistently disrupt circadian rhythms, and circadian disruptions are strongly associated with delirium. Exposure to benzodiazepines and constant light are suspected risk factors for the development of delirium. Thus, we tested the functional role of the circadian rhythm protein Period 2 (PER2) in different mouse models resembling delirium. DESIGN: Animal study. SETTING: University experimental laboratory. SUBJECTS: Wildtype, Per2 mice. INTERVENTIONS: Midazolam, lipopolysaccharide (lipopolysaccharide), constant light, nobiletin, or sham-treated animals. MEASUREMENTS AND MAIN RESULTS: Midazolam significantly reduced the expression of PER2 in the suprachiasmatic nucleus and the hippocampus of wild-type mice. Behavioral tests following midazolam exposure revealed a robust phenotype including executive dysfunction and memory impairment suggestive of delirium. These findings indicated a critical role of hippocampal expressed PER2. Similar results were obtained in mice exposed to lipopolysaccharide or constant light. Subsequent studies in Per2 mice confirmed a functional role of PER2 in a midazolam-induced delirium-like phenotype. Using the small molecule nobiletin to enhance PER2 function, the cognitive deficits induced by midazolam or constant light were attenuated in wild-type mice. CONCLUSIONS: These experiments identify a novel role for PER2 during a midazolam- or constant light-induced delirium-like state, highlight the importance of hippocampal PER2 expression for cognitive function, and suggest the PER2 enhancer nobiletin as potential therapy in delirium-like conditions associated with circadian disruption.