Obesity is associated with a variety of adverse health risks. Several genome-wide association studies of obesity have identified candidate genes, including the fat mass and obesity-associated gene (FTO) and the melanocortin-4 receptor (MC4R) gene. We carried out a replication study of MC4R and FTO variants in a Korean cohort. A total of 2,281 subjects in the Bundang-gu region were analyzed using selected markers. Another 8,826 subjects in the Ansung/Ansan city were used for a meta-analysis. Two single nucleotide polymorphisms (SNPs) in FTO and one SNP in the MC4R gene were genotyped. Multivariate linear regression models were employed to test for genotypic effects on obesity traits while adjusting for age and sex using an additive model. The SNP rs17782313 near the MC4R gene was associated with mean body mass index in the Bundang-gu cohort (effect per allele 0.288 kg/m(2), p = 0.0023). The p value for meta-analysis of rs17782313 in all 11,107 individuals in the Bundang-gu and Ansung/Ansan cohorts was 2.82 × 10(-6) (effect per allele 0.22 kg/m(2)). Two SNPs in FTO were significantly associated with weight (effect per allele 0.969 kg, p = 0.011 for rs9939609; 0.943, p = 0.014 for rs8050136) but not with body mass index. This study demonstrates that genetic variants in MC4R influence obesity traits in Korean adults.