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Background: Functional TRIB3 Q84R polymorphism has been associated with insulin resistance. Obestatin, improving insulin resistance, exerts obscure effects on metabolic syndrome (MetS) and carotid atherosclerosis. Aims to investigate whether the prevalent TRIB3 Q84R polymorphism has profound implications for alterations of serum obestatin and what effect obestatin exerts on carotid atherosclerosis. Methods: A total of 518 unrelated Chinese subjects consisted of control (n = 258) and MetS (n = 260) groups. Clinical and biochemical characteristics were collected. The level of serum obestatin was measured. Genotype the functional TRIB3 Q84R polymorphism. All subjects underwent ultrasonography to determine carotid intima-media thickness (IMT). Results: Serum obestatin was significantly decreased in MetS as compared with the control group (P = 0.042). Among the MetS group participants possessing RR84 genotype had significantly lower levels of serum obestatin than those with QQ84 or QR84 genotypes (P = 0.008, P = 0.043) with similar significant difference among the control group. Factorial analyses showed statistically significant interactions between MetS and RR84 genotype (P = 0.009 for interaction for obestatin). On correlation analysis, obestatin correlated negatively with homeostasis model assessment insulin resistance (r = -0.163, P = 0.010) and IMT (r = -0.256, P = 0.011). On partial analyses, obestatin negatively correlated with IMT(r = -0.259, P = 0.024) after controlling for the confounding factors. Conclusion: MetS individuals with TRIB3 RR84 genotype demonstrated further decreased serum obestatin. Decreased serum obestatin might in part exacerbate insulin resistance and carotid atherosclerosis. [ABSTRACT FROM AUTHOR]