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Background: As the prevalence of obesity has steadily increased, it has rapidly emerged as a major public health concern due to a high risk of morbidity and mortality. Rare missense and nonsense mutations in the melanocortin-4 receptor (MC4R) gene are a cause of genetic forms of severe obesity, and targeted disruption of the mouse MC4R leads to obesity. The role of variation at the MC4R locus in influencing interindividual variation in body size and composition in the general population is controversial.Objective: To test the hypothesis that polymorphic variation at the MC4R locus is significantly associated with measures of adiposity in the general population.Methods: Two single nucleotide polymorphisms, -4599 T>G and -4850 T>C, in the 5¡¯-flanking region of MC4R were verified by resequencing in 16 individuals and genotyped in the larger sample by fluorescence polarization. 1,099 healthy, non-Hispanic white volunteers, age 30-54 years, were recruited from the Pittsburgh community. A medical and demographic history was collected and anthropomorphic measures were determined. ANOVA was used to assess the relationship between genotype and metabolic parameters.Results: BMI was greater in participants having a -4599 G allele (GG + TG genotypes) than among TT homozygotes (p < 0.03), and this association was of similar magnitude in both men (BMI 28.2 vs. 27.4) and women (BMI 26.5 vs. 25.9). Nominally defined overweight (BMI ¡Ý 27) also varied significantly (Chi-square = 6.874, p < 0.04) across -4599 genotypes (GG: 52.4%; TG: 46.8%, TT: 40.6%). A similar relationship was seen for the -4850 T>C SNP (CC: 53.2%; TC: 48.0%; TT: 41.4%; Chi-square = 6.256, p < 0.05). Finally, subjects with any -4599 G allele had significantly higher weight (177.0 vs. 172.8; p < 0.05) and percent of body fat (29.8% vs. 28.8%; p < 0.04). Greater waist circumference was also significantly associated with both the -4599 G allele (36.3 vs. 35.6; p < 0.04) and the -4850 C allele (36.4 vs. 35.6; p < 0.0