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Objectives This study aimed to investigate whether plasma levels of adenosine, adenosine deaminase (ADA), and certain cytokines change in patients with chronic insomnia disorder (CID), and if so, whether these alterations are associated with poor sleep quality and cognitive dysfunction. Methods Fifty-five CID patients were selected for the study, along with fifty-five healthy controls (HC) matched to the patients according to their basic data. All subjects completed sleep, emotion, and cognition assessments, with some CID patients also completing an overnight polysomnography. The plasma level of adenosine was measured using liquid chromatography–tandem mass spectrometry, while ADA level was quantified using a quantitative sandwich enzyme-linked immunosorbent assay. Levels of cytokines, including IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, TNF-α, and IFN-γ, were measured using Luminex liquid chip technology. Results CID patients had a lower adenosine level, and higher levels of ADA and some of the cytokines (IL-1β, IL-2, IL-6, IL-10 and TNF-α) compared with controls. In the CID group, plasma concentrations of adenosine were negatively correlated with Pittsburgh Sleep Quality Index scores, while concentrations of IL-1β, IL-6 and TNF-α were positively correlated with these scores. Concentrations of IL-1β and TNF-α were negatively correlated with scores on the Chinese-Beijing Version of the Montreal Cognitive Assessment. Moreover, levels of IL-1β, TNF-α, IL-6, and IL-2 were positively correlated with memory test errors by CID patients after controlling for confounding factors. Conclusions The reduced adenosine and elevated cytokine levels of CID patients were associated with the severity of insomnia and/or cognitive dysfunction.