IMPORTANCE: Genes may work by modulating the way individuals respond to environmental variation, and these discrete and differential genes vs environmental interactions may not be readily captured in simple association studies. OBJECTIVE: To determine whether children carrying the 7-repeat allele of the DRD4 gene living under adverse economic conditions have worse-than-average fat intake compared with those living in a healthy environment. DESIGN, SETTING, AND PARTICIPANTS: Data from an established prospective birth cohort (Maternal Adversity, Vulnerability, and Neurodevelopment) were used to study 4-year-old children from Montreal, Quebec, Canada and Hamilton, Ontario, Canada. A total of 190 children (94 girls and 96 boys) had height and weight measured and complete food diaries and were therefore eligible for the study. The study is derived from a birth cohort started in June 2003 and still ongoing. The last age of follow-up was at 6 years. EXPOSURES: Social environment was characterized based on the gross family income, and DNA was genotyped for the 7-repeat allele of the DRD4 gene. MAIN OUTCOMES AND MEASURES: Fat intake. RESULTS: The 5 steps to distinguish the differential susceptibility from other types of interaction were followed, and the study confirms that differential susceptibility is a relevant model to address the association between the 7-repeat allele of DRD4 and food choices in girls. Of the 190 children, 112 did not have the DRD4 7-repeat allele and 78 did. Baseline characteristics did not differ in these 2 groups. Although not different in several confounders, such as maternal educational level, maternal smoking during gestation, birth weight, and breastfeeding duration, girls carrying the 7-repeat allele of the DRD4 gene and living in adverse socioeconomic conditions have increased fat intake compared with girls who are noncarriers (DRD4 7+ mean, 33.95% of calories derived from fat; 95% CI, 28.76%-39.13%; DRD4 7- mean, 28.76%; 95% CI, 26.77%-30.83%). However, girls carrying the 7-repeat allele of the same gene and living in better socioeconomic conditions have decreased fat intake compared with noncarriers (DRD4 7+ mean, 29.03% of calories derived from fat; 95% CI, 26.69%-31.51%; DRD4 7- mean, 31.88%; 95% CI, 30.28%-33.58%). CONCLUSIONS AND RELEVANCE: Alleles previously considered to be obesity risk alleles might in fact function as plasticity alleles, determining openness to environmental modification and/or intervention, as seen in the girls in this study. This finding has important implications for obesity prevention and social pediatrics.