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Here, we report that afternoon LPS challenges in mice induce a robust inflammatory response involving increased neutrophil activation and release of cytotoxic mediators, causing higher mortality compared with challenges at midnight. Mechanistically, the cyclic patterns of corticosterone and melatonin hormones differentially modulate neutrophil responses. The afternoon corticosterone peak was associated with heightened incidence and severity of LPS\u2010induced hyperinflammation. Conversely, higher melatonin levels at midnight conferred protection to challenged mice by restraining the magnitude of inflammation. High cortisol and low melatonin profiles detected in septic patients mirror those observed in mice and suggest a novel prognostic marker for sepsis. 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