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Purpose: Tsukushi (TSK), a novel hepatokine, has recently been pointed out to play an important role in energy homeostasis and glycolipid metabolism. However, there are no clinical studies on the association of TSK with metabolic syndrome (MetS), the typical constellation of metabolic disorders. This study was conducted to explore the relationship between TSK and MetS as well as each of its metabolic component clinically. Methods: We analyzed in this cross-sectional study serum TSK levels by ELISA in 392 participants, including 90 non-MetS and 302 MetS, to compare TSK in two groups and in different numbers of metabolic components. The odds ratios (OR) of TSK quartile in MetS and each metabolic component were computed by multivariate logistic regression analysis. Results: TSK was substantially higher in MetS than in non-MetS subjects (P< 0.001). TSK increased with the concomitant increase of the number of metabolic components (Pfor <0.001). Logistic regression analyses demonstrated that the OR of MetS was 2.74 for the highest versus the lowest quartile of TSK (P< 0.001) after adjusting for age, gender, smoking status, alcohol consumption and medication use. Additionally, TSK was associated with the OR of poor HDL-C and elevated fasting glucose (P< 0.05). Conclusion: Circulating TSK was higher in MetS patients and linked with MetS risk, suggesting that TSK may play a role in the genesis of MetS and be a potential therapeutic target for MetS. Future study should investigate the connection between TSK levels and MetS pathogenesis.