Six rare functional coding mutations were previously identified in melanocortin 4 receptor ( MC4R) in 6,760 American Indians. Individuals heterozygous for one of these mutations become obese while young. We now investigate whether common non-coding variation near MC4R also contributes to obesity. Fifty-six tag single-nucleotide polymorphisms (SNPs) were genotyped in 3,229 full-heritage Pima Indians, and nine of these SNPs which showed evidence for association were genotyped in additional 3,852 mixed-heritage American Indians. Associations of SNPs with maximum body mass index (BMI) in adulthood ( n = 5,918), BMI z score in childhood ( n = 5,350), percent body fat ( n = 864), energy expenditure ( n = 358) and ad libitum food intake ( n = 178) were assessed. Conditional analyses demonstrated that SNPs, rs74861148 and rs483125, were independently associated with BMI in adulthood ( β = 0.68 kg/m per risk allele, p = 5 × 10; β = 0.58 kg/m, p = 0.002, respectively) and BMI z score in childhood ( β = 0.05, p = 0.02; β = 0.07, p = 0.01, respectively). One haplotype (frequency = 0.35) of the G allele at rs74861148 and the A allele at rs483125 provided the strongest evidence for association with adult BMI ( β = 0.89 kg/m, p = 5.5 × 10), and was also associated with childhood BMI z score ( β = 0.08, p = 0.001). In addition, a promoter SNP rs11872992 was nominally associated with adult BMI ( β = 0.61 kg/m, p = 0.05) and childhood BMI z score ( β = 0.11, p = 0.01), where the risk allele also modestly decreased transcription in vitro by 12 % ( p = 0.005). This risk allele was further associated with increased percent body fat ( β = 2.2 %, p = 0.002), increased food intake ( β = 676 kcal/day, p = 0.007) and decreased energy expenditure ( β = −53.4 kcal/day, p = 0.054). Common and rare variation in MC4R contributes to obesity in American Indians. [ABSTRACT FROM AUTHOR]