Context: Very recently, unforeseen role of syndecan 3 (SDC3), a family of membrane-bound heparin sulfate proteoglycans, in the regulation of energy balance has been discovered in the Sdc3 null female mice. Objective: To test the hypothesis that single nucleotide polymorphisms (SNPs) in SDC3 are associated with obesity in Korean population. Design/Setting/Subjects: Population-based cohort study consisting of 229 control and 245 study subjects and second independent study consisting of 192 control and 115 study subjects. Main outcome measurement: Body mass index (BMI). Results: Firstly, Sdc3 mRNA expression in the brain of ob/ob mice was profoundly increased compared with control mice. Next, all three nonsynonymous SNPs (T271I [rs2282440, C>T], D245N [rs4949184, C>T], and V150I [rs2491132, C>T]) in SDC3 gene in control female subjects (BMI<23, n = 229) and obese female subjects (BMI>30, n = 245) were genotyped. We demonstrated the presence of clear ethnic differences in three nonsynonymous SDC3 SNPs among African Americans, Chinese, Europeans, and Koreans. Of three SNPs in SDC3, rs4949184 was not associated with obesity and the other two SNPs (rs2282440 and rs2491132) were strongly associated with obesity (P < 0.0001) and the results were confirmed in the second independent study group. Haplotype analysis also revealed strong association with obesity (²=76.92, P < 0.000001). Conclusions: There are ethnic differences in the SDC3 polymorphisms and the polymorphisms are strongly associated with obesity.