To elucidate the role of modifiable factors and the apolipoprotein E polymorphism in explaining lipid profiles reflecting low, average and high risk for coronary heart disease, we selected subjects from a large population-based study. Subjects with low total cholesterol (TC) (< 15th percentile) and high HDL-cholesterol levels (> 85th percentile) were randomly selected (n = 99) and represent subjects with a low risk lipid profile. Additionally, 95 subjects with total and HDL-cholesterol levels in the 15% around the population-median (median risk lipid profile) and 100 subjects with high TC (> 85th percentile) and low HDL-cholesterol levels (< 15th percentile) (high risk lipid profile) were selected. Compared with E3/3 subjects, the likelihood for a low risk lipid profile was considerably higher (odds ratio 14.3; 2.6-79) in female, but not in male E2-carriers (1.5; 0.3-6.7). Smoking and alcohol consumption were independently associated with a low risk lipid profile in both genders, physical inactivity only in women. The odds ratio for a high risk lipid profile was elevated in male E4-carriers (4.9; 1.1-23) only. In addition to the E4 isoform, smoking and physical inactivity, overweight was the main determinant for a high risk lipid profile (odds ratio 16.8; 3.4-82). Male overweight E4-carriers had a 50 times higher likelihood of a high risk lipid profile than E3/3 men of normal weight. In women, only overweight was independently associated with a high risk lipid profile. Our results suggest that both modifiable factors and the apolipoprotein E polymorphism contribute to a lipid profile, reflecting low, average and high risk for coronary heart disease, but effects may be gender-specific.