The aim of this study was to determine the effect of dietary quercetin supplementation on blood lipids and TNF-α levels according to the apoE genotype in apoE3 and apoE4 targeted gene replacement mice. In a two-factorial design female apoE3 and apoE4 mice were fed semi-synthetic diets without (controls) and with quercetin (2 mg/g diet) for 6 weeks. Feeding the quercetin-supplemented diets significantly increased plasma levels of quercetin and isorhamnetin both in apoE3 and apoE4 mice. There was no significant effect of apoE genotype on plasma quercetin levels. ApoE3 and apoE4 transgenic mice exhibited similar plasma levels of apoE and cholesterol which were not significantly affected by dietary quercetin supplementation. In mice receiving the basal diet without quercetin supplementation, levels of TNF-α in whole blood stimulated ex vivo with lipopolysaccharide were higher in apoE3 as compared to apoE4 transgenic mice. Dietary quercetin significantly lowered levels of TNF-α by 44 % in apoE3 mice relative to apoE3 mice receiving the unsupplemented diets. In apoE4 mice a moderate (20 %) but not significant decrease in TNF-α levels in response to the quercetin supplementation was evident. Following quercetin supplementation TNF-α levels were similar between apoE3 and apoE4 transgenic mice. Current findings indicate that apoE3 mice are more responsive to the TNF-α lowering properties of dietary quercetin supplementation as compared to apoE4 animals.