The interindividual variation in ApoE plasma concentration is considerable, mainly determined by apoE genotype and sex. However, a large amount of variability remains unexplained by these factors. We have evaluated whether the quantity and quality of dietary fat interacts with the apoE genotype and sex modifying ApoE plasma levels in young healthy subjects. Eighty-four volunteers (sixty-six apoE3/3, eight apoE4/3 and ten apoE3/2) were subjected to three dietary periods, each lasting 4 weeks. The first was a SFA-enriched diet (38 % fat and 20 % SFA), which was followed by a carbohydrate (CHO)-rich diet (30 % fat, < 10 % SFA and 55 % carbohydrate) or a MUFA-rich diet (38 % fat and 22 % MUFA) following a randomised crossover design. apoE2 carriers have the highest ApoE levels, whereas apoE4 individuals show the lowest concentration after the SFA, CHO and MUFA diets. Women had significantly higher ApoE concentration than men only after the consumption of the SFA diet. The SFA diet increased the ApoE plasma concentration when compared with the CHO- and MUFA-rich diets in women, but not in men. In women, but not in men, the shift from the SFA- to CHO- or MUFA-rich diets significantly decreased the ApoE concentration in apoE3/2 and apoE3/3 subjects, whereas no differences were observed in women with the apoE4/3 genotype. Sex and apoE genotype determine ApoE plasma levels; however, this effect is dependent on dietary fat.