OBJECTIVE Recent study showed high chemokine CXC ligand 5 (CXCL5) is thought to be associated with insulin resistance in humans. However, evidence from large-scale populations about the relationship between serum CXCL5 level and metabolic phenotypes is scarce. Here we sought to evaluate serum CXCL5 distribution and its association with metabolic phenotypes among middle-aged and older Chinese. RESEARCH DESIGN AND METHODS We evaluated serum CXCL5 in a cross-sectional sample of 3225 Chinese aged from 50 to 88 yr in a Shanghai downtown district by ELISA. Glucose, insulin, lipid profile, inflammatory marker, and adipokine were also measured. RESULTS The crude mean of serum CXCL5 concentrations were 1493.31 pg/ml for men and 2059.42 pg/ml for women (P<0.001), respectively. After multiple adjustment, the odds ratios were substantially higher for hypercholesterolemia (odds ratio 3.26, 95% confidence interval 2.36-4.51) in the highest CXCL5 quartile compared with those in the lowest quartile. These associations remained significant after further adjustment for body mass index, body fat, inflammatory marker, and adipokine. However, serum resistin CXCL5 was not associated with body mass index, percent body fat, fasting glucose, insulin levels, and homeostasis model assessment index-insulin resistance (r=0.01, 0.01, 0.01, 0.04, and 0.03, respectively; all P>0.05). CONCLUSIONS Elevated circulating CXCL5 concentrations were associated with higher risk of hypercholesterolemia in middle-aged and elderly Chinese independent of obesity, inflammation, adipokines, and other risk factors but not insulin resistance.