Background: TFAP2B rs987237 is associated with obesity and has shown interaction with the dietary fat-to-carbohydrate ratio, which has an effect on weight loss. We investigated interactions between rs987237 and protein-to-carbohydrate ratio or glycemic index (GI) in relation to weight maintenance after weight loss. Methods: This study included 742 obese individuals from 8 European countries who participated in the Diet, Obesity, and Genes (DiOGenes) trial, lost ≥8% of their initial body weight during an 8-week low-calorie diet and were randomized to one of 5 ad libitum diets with a fixed energy percentage from fat: either low-protein/low-GI, low-protein/high-GI, high-protein/low-GI, or high-protein/high-GI diets, or a control diet for a 6-month weight maintenance period. Using linear regression analyses and additive genetic models, we investigated main and dietary interaction effects of TFAP2B rs987237 in relation to weight maintenance. Results: In total, 468 completers of the trial were genotyped for rs987237. High-protein diets were beneficial for weight maintenance in the AA genotype group (67% of participants), but in the AG and GG groups no differences were observed for low- or high-protein diets. On the high-protein diet, carriers of the obesity risk allele (G allele) regained 1.84 kg (95% CI: 0.02; 3.67, p = 0.047) more body weight per risk allele than individuals on a low-protein diet. There was no interaction effect between rs987237 and GI on weight maintenance. Conclusion: TFAP2B rs987237 and dietary protein/carbohydrate interacted to modify weight maintenance. Considering the carbohydrate proportion of the diet, the interaction was different from the previously reported rs987237-fat-to-carbohydrate ratio interaction for weight loss. Thus, TFAP2B-macronutrient interactions might diverge depending on the nutritional state. © 2013 S. Karger AG, Basel.