The microsomal triglyceride transfer protein (MTP) plays a key role in the secretion of apolipoprotein B (apoB)-containing lipoproteins. The rare variant of a functional polymorphism in the promoter region of the MTP gene has been associated with elevated transcriptional activity of the gene in vitro (MTP-493G/T). With use of a "recruit-by-genotype" approach, we investigated one of the potentially complex phenotypes of this polymorphism, the appearance in plasma of apoB-48 after a meal intake. A total of 12 homozygous carriers of the rare MTP-493T variant were identified from a population-based screening of 50-year-old healthy white men. All subjects were of the apoE3/3 genotype. Along with 48 baseline well-matched heterozygotes (n=24) plus homozygotes (n=24) for the common variant, they were given a standardized oral fat meal. Postprandial plasma concentrations of apoB-48 were determined by the combination of density gradient ultracentrifugation and analytical SDS-PAGE. The postprandial plasma concentrations of triglycerides did not differ between the groups, but homozygous carriers of the rare MTP-493T variant showed a >100% greater increase in apoB-48 in the smallest (Svedberg flotation rate constant 20 to 60) triglyceride-rich lipoprotein fraction (P=0.005). These data support the notion that elevated transcriptional activity of MTP leads to an increased generation of the smallest triglyceride-rich lipoprotein from the intestine.