Objective: Variants downstream of the melanocortin-4 receptor gene (MC4R) have been reported to associate with obesity. We examined rs17782313, rs17700633, rs12970134, rs477181, rs502933, and rs4450508 near MC4R for association with obesity-related quantitative traits, obesity, and type 2 diabetes in Danish individuals. Research Design and Methods: The variants were investigated for association with obesity-related quantitative traits in 5,807 population-based-sampled individuals, for association with obesity in 14,940 individuals, and for association with type 2 diabetes in 8,821 individuals. Results: The minor risk alleles of rs17782313, rs17700633, and rs12970134 associated with BMI (effect per-allele: 0.25 [P=0.01], 0.23 [P=0.01], and 0.31 [P=7x10(-4)] kg/m(2), respectively); waist circumference (effect per-allele: 0.67 [P=0.006], 0.53 [P=0.02], and 0.85 [P=3x10(-4)] cm, respectively); and body weight (effect per-allele: 1.04 [P=6x10(-4)], 0.71 [P=0.01], and 1.16 [P=8x10(-5)] kg, respectively). In case-control studies of obesity defined by BMI the minor C-allele of rs17782313 associated with overweight/obesity and obesity (OR(overweight/obesity)=1.09, P=0.006; OR(obesity)=1.12, P=0.003). Similarly, the minor A-allele of rs17700633 associated with overweight/obesity and obesity (OR(overweight/obesity)=1.12, P=8x10(-5); OR(obesity)=1.16, P=2x10(-5)), and the minor A-allele of rs12970134 was also associated with overweight/obesity and obesity (OR(overweight/obesity)=1.13, P=2x10(-5); OR(obesity)=1.15, P=6x10(-5)). rs477181, rs502933, and rs4450508 were not statistically significantly associated with obesity in the Danish population. The frequency of the minor risk alleles of rs17782313 and rs12970134 were higher among patients with type 2 diabetes compared with glucose-tolerant individuals (OR=1.08, P=0.08; and OR=1.08, P=0.06, respectively); however, these borderline associations were abolished after adjustment for BMI. Conclusions: rs17782313, rs17700633, and rs12970134 near MC4R associate with measures of obesity in Danish individuals.