Cholesterol homeostasis is essential for functional integrity of lipid. Niemann-Pick disease, type C2 (NPC2) encodes a protein containing a lipid recognition domain. NPC2 is related to regulation of cholesterol and other lipids. To evaluate NPC2 gene and its correlation to obesity in Korean population, 214 overweight/obese and 160 healthy control subjects were enrolled in this study. Genomic DNA was extracted from peripheral blood. Two tag single nucleotide polymorphisms (tag SNPs) in NPC2 gene were selected (rs8008540 and rs917394). Genotypes were determined using direct sequencing. For the analysis of genetic data, Helixtree software, SNPAnalyzer, SNPStats, and Haploview version 4.2 were used. Multiple logistic regression models (codominant, dominant, and recessive models) were performed for odds ratio (OR), 95% confidence interval (CI), and P value. In allele distribution analysis, allele of rs917394 was associated with obesity (OR=1.45, 95% CI=1.08-1.95, P=0.014). The genotype distributions of tag SNPs (rs8008540 and rs917394) were showed significant differences between overweight/obese and control subjects [rs8008540, OR=1.63, 95% CI=1.04-2.58, P=0.034 in codominant 1 (C/C versus C/T) model, OR=1.58, 95% CI=1.03-2.44, P=0.036 in dominant model; rs917394, OR=2.33, 95% CI=1.20-4.52, P=0.013 in codominant model 2 (T/T versus C/C), OR=1.62, 95% CI=1.05-2.52, P=0.030 in dominant model]. Haplotype (CT) was also associated with overweight/obese (frequency=0.589, chi square=6.100, P=0.014). These results indicate that NPC2 gene may be associated with obesity in Korean population.