BACKGROUND High retinol-binding protein 4 (RBP4) is thought to be associated with insulin resistance in humans. However, evidence from large-scale populations about the relationship between RBP4 and metabolic diseases is scarce. OBJECTIVE We evaluated plasma RBP4 distribution and its association with metabolic syndrome (MetS) among middle-aged and older Chinese. METHODS We evaluated plasma RBP4 in a cross-sectional sample of 3289 Chinese aged from 50 to 70 yr in Beijing and Shanghai by using an in-house developed and validated sandwich ELISA. MetS was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian-Americans. RESULTS RBP4 levels were higher in male and Beijing residents, compared with female and Shanghai participants (both P < 0.001). RBP4 levels were associated positively with body mass index, waist circumference, triglycerides, total and low-density lipoprotein cholesterol, blood pressure, fasting insulin, and homeostatic model assessment of insulin resistance and negatively with high-density lipoprotein cholesterol and adiponectin (all P < 0.001). In the highest RBP4 quartile, the MetS risk was significantly higher (odds ratio 2.58; 95% confidence interval 2.08-3.20) than in the lowest quartile after adjustment for potential confounders. This association remained strong (odds ratio 2.25; 95% confidence interval 1.72-2.94) after further controlling for C-reactive protein, adiponectin, homeostatic model assessment of insulin resistance, and body mass index. CONCLUSIONS This first large-scale population study shows that elevated RBP4 levels are strongly and independently associated with MetS. Prospective studies are needed to establish the role of RBP4 in the development of MetS and related diseases.