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Increased levels of physical activity may improve the lipid profile, but is this effect identical across apolipoprotein E (apoE) genotypes? A population-based cross-sectional survey conducted from 1999 to 2000 included 1708 randomly selected men and women aged 35 to 74 years. A validated physical activity questionnaire measured, for each participant, the total energy expenditure and its percentage used in high-intensity activities (%high-intensity activity), eg, brisk walking and sports. The effects of the apoEx%high-intensity activity interaction on the lipid profile were investigated by using multiple linear regression models. Among men, increased %high-intensity activity had greater protective effects in the apoE4 group regarding (1) high density lipoprotein (HDL) cholesterol (P<0.001), compared with either the apoE2 (interaction P=0.05) or apoE3 (interaction P<0.03) groups, and (2) triglycerides (P<0.03), compared with the apoE3 group (interaction P=0.07). A 10% increase of %high-intensity activity by an apoE4 man would correspond with a 0.07-mmol/L increase in HDL cholesterol and a -0.15-mmol/L decrease in triglycerides. Among women, only the protective effects of physical activity on HDL cholesterol in the apoE4 group versus the apoE2 group was statistically significant. Spending a larger fraction of the total energy expenditure in high-intensity activities may counteract the atherogenic effects of the epsilon4 allele on the lipid profile.