Background Differences in serum lipid distribution and mortality from ischaemic heart disease have repeatedly been reported between Belgian northerners and southerners. We investigated whether serum lipoprotein(a) (Lp(a)) and apolipoprotein (apo) F polymorphism were involved. Methods Fasting serum lipids, apo A-I and B, and Lp(a) levels were examined in randomly selected, 20–39 year old Belgian males and females from the north (Flanders) and the south (Wallonia) of Belgium (N = 900). Apo E phenotype distribution was investigated in random subsamples from either region (N = 249). Results Mean serum cholesterol, low density lipoprotein cholesterol (LDL-c), apo B and triglyceride levels were higher in Walloons compared to Flemings within each gender, the difference being significant in 30–39 year old males. Average high density lipoprotein cholesterol and apo A-I levels were significantly lower in 30–39 year old male southerners, compared to their northern counterparts. Median Lp(a) was 67 mg/I in northerners and 75 mg/l in southerners (NS). The apo E phenotype distribution was similar in both regions ( x 2 = 7.213; d.f. = 5; P = 0.2053), whereas the average effects of the apo E alleles differed between the regions. In southerners the ε4 effect upon adjusted apo B and LDL-c levels was ≈+12% and the ε2 effect was ≈−15% in northerners the ε4 and ε2 effects were ≈+5% and ≈ −25%, respectively. The apo F polymorphism did not affect serum Lp(a) levels. Conclusions Regional cholesterol differences between Flemings and Walloons cannot be explained by differences in serum Lp(a) or apo E phenotype distribution. The less favourable ε2 and ε4 effects in southerners compared to northerners reflect modulation of the apo E gene by particular environments.