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Background: The central melanocortin system is critical for the long-term regulation of energy homeostasis. Melanocortin-3 receptor (MC3R) knock-out mice, despite being hypophagic, have increased fat mass and higher feed efficiency than do their wild-type littermates. Objective: The aim was to evaluate whether, in childhood obesity, MC3Rvariants are associated with changes in fatness reduction as a consequence of a weight-reduction program. Design: Molecular screening of the MC3R coding region in 184 obese children, 77 girls and 107 boys [x (SEM) body mass index (BMI; in kg/m 2 ) z score: 3.3 2.3; age 9.2 2 y], was performed. BMI was evaluated at baseline and after 6 and 12 mo of the weight loss program. Results: No new mutations were found. Two previously described polymorphisms, C17A (Thr6Lys) and G241A (Val81Ile), were observed in 20 patients in almost complete linkage disequilibrium. No significant differences in BMI z scores were observed at baseline of theweight-lossprogrambetweenthegenotypes;however,atfollowup, heterozygotes showed a significantly higher BMI z score (P 0.03). When the patients were divided according to the amount of weight lost, a higher prevalence of heterozygotes was observed among subjects who lowered their BMI z score 1.5 (P 0.03). Conclusion: These results suggest a gene-diet interaction between theMC3RC17A and G241A variants and a weight loss program for the ability to lose weight in childhood obesity. Am J Clin Nutr 2007;85:950–3.