OBJECTIVE: Fibroblast growth factor 21 (FGF21) levels have been linked with beneficial effects on glucose and lipid metabolism in animals. It is elevated in humans with the metabolic syndrome. This study investigates independent factors associated with serum FGF21 levels. DESIGN: Cross-sectional study done in healthy blue-collar workers. METHODS: A medical history was taken, and FGF21 (measured using an ELISA commercial kit), glucose, uric acid, plasma lipids, total/high-molecular weight (HMW) adiponectin, and retinal-binding protein 4 (RBP4) were measured in 210 individuals with (n=81) and without (n=129) metabolic syndrome. RESULTS: The median of serum FGF21 levels were higher in subjects with metabolic syndrome (339.5 vs 276.4 ng/l, P=0.01). Serum FGF21 levels correlated positively with body mass index (BMI; r=0.23, P=0.001) and age (r=0.17, P=0.01). After adjusting for age and BMI, a significant positive correlation persisted for fasting glucose, uric acid, and physical activity in both males (r=0.21, r=0.11, and r=0.19, all P<0.05) and females (r=0.20, r=0.19, and r=0.14, all P<0.05). In addition, FGF21 also correlates negatively with RBP4 (r=-0.27, P=0.02), total (r=-0.26, P=0.03), and HMW adiponectin (r=-0.30, P=0.01) in women. A multiple linear regression model analysis identified that BMI (standardized beta (SB)=0.247; P=0.008), glucose (SB=0.226; P=0.003), uric acid (SB=0.191; P=0.04), and physical activity (SB=0.223; P=0.004) are independent factors influencing serum FGF21 levels (F=10.05, r(2)=0.19, P<0.001). In addition, fasting hyperglycemia > or =100 mg/dl, excess body weight with BMI > or =25 kg/m(2), and uric acid > or =5.5 mg/dl predicted higher serum FGF21 levels. CONCLUSION: Serum FGF21 levels are influenced by BMI, fasting glycemia, uric acid, and physical activity.