The melanocortin-4 receptor (MC4R) is an essential regulator of food intake and energy homeostasis. Previous data suggest an influence of MC4R activity on TAG levels. Thus, the aim of the present study was to determine whether the presence of the rs12970134 polymorphism near the MC4R gene could influence postprandial lipoprotein metabolism in healthy subjects. A total of eighty-eight volunteers were selected, fifty-three homozygous for the common genotype (G/G) and thirty-five carriers for the minor A-allele (G/A and A/A). They were given a fat-rich meal containing 1 g fat and 7 mg cholesterol/kg body weight and vitamin A (60 000 IU/m2 body surface). Fat accounted for 60 % of energy, and protein and carbohydrates accounted for 15 and 25 % of energy, respectively. Blood samples were taken at time 0, every 1 h until 6 h and every 2·5 h until 11 h. Total cholesterol and TAG in plasma, and cholesterol, TAG and retinyl palmitate in TAG-rich lipoproteins (TRL, large and small TRL) were separated by ultracentrifugation. Individuals carrying the G/G genotype displayed a higher postprandial response of plasma TAG (P = 0·033), total cholesterol (P = 0·019) and large TRL–TAG (P = 0·023) than did carriers of the minor A-allele. Furthermore, G/G subjects showed a greater postprandial response of small TRL–apoB48 than did carriers of the A-allele (P = 0·032). These results suggest that the rs12970134 polymorphism near the MC4R gene region may partly explain the inter-individual differences in postprandial lipoprotein response in healthy subjects.