Background-Although much is known about the effect of Apolipoprotein E (APOE) alleles on fasting lipid concentrations, less is known about the effect of APOE alleles on postprandial triglyceridemia or the triglyceride response to fenofibrate. Methods and Results-We evaluated the effects of the APOE locus on fasting and postprandial triglyceride concentrations as part of the Genetics of Lipid Lowering and Diet Network (GOLDN) study. Participants were evaluated after a high-fat meal challenge before (n=1072) and after 3 weeks of daily treatment with 160 mg of fenofibrate (n=738). Mixed models adjusted for sex, age, waist circumference, and family relationship were used to examine the association of the ε4 carrier and ε2 carrier status versus ε3 homozygotes with fasting triglycerides and the area under the curve (AUC) for triglycerides during the high-fat meal challenge. Compared with the e3/e3 genotype, ε2 carriers had on average higher fasting triglyceride concentrations (130.5 mg/dL versus 109.3 mg/dL, P<0.001). After fenofibrate treatment, the APOE genotype differences persisted in the fasting state (ε2 carriers: 85.1 mg/dL versus ε3/ε3: 75.9 mg/dL, P<0.05). Carriers of the ε4 allele had significantly higher fasting triglyceride concentrations only prefenofibrate (120.9 mg/dL versus 109.3 mg/dL, P= 0.008). APOE alleles did not have an effect on response to fenofibrate. Postprandial triglycerides were significantly higher for ε2 carriers versus ε3 homozygotes (but not ε4 carriers) both before and after fenofibrate treatment (P=0.01 and P=0.005, respectively). Conclusions-APOE polymorphisms are important determinants of triglyceride concentrations, especially in the fasting state.