Obesity is highly heritable, but the specific genes influencing obesity related traits are largely unknown. Fibroblast growth factor 2 (FGF2) could influence adipocyte differentiation. However, the association of FGF2 polymorphisms and obesity remains unclear. This study aimed to investigate the associations of both the plasma FGF2 levels and SNPs in FGF2 gene with obesity phenotypes in Han Chinese populations. Plasma FGF2 levels were measured and subjected to association analyses in 62 subjects. Eleven SNPs in FGF2 were genotyped and tested for associations in a discovery sample of 1,300 subjects. SNPs significantly associated with obesity were subjected to replication in another independent sample of 1,035 subjects. We found that plasma FGF2 levels were positively correlated with fat mass (P = 0.010). Association analyses in the discovery sample identified three SNPs (rs1449683, rs167428, rs308442) significantly associated with fat mass after multiple testing adjustments (P < 0.0045). Subsequent replication study successfully validated one SNP (rs167428) associated with fat mass (P(combine) = 3.46 × 10(-5)). eQTL analyses revealed that SNPs associated with obesity also affected FGF2 expression. Our findings suggested that high plasma FGF2 level correlated with increased risk of obesity, and FGF2 gene polymorphisms could affect individual variances of obesity in Han Chinese population.