To evaluate the influence of birth weight on apolipoprotein (apo) E genetic determinants of plasma lipids levels in prepubertal children we studied 933 healthy children (491 males and 442 females) 6 to 8 years old (mean age of 6.7 y), whose weight was recorded at birth. Plasma lipid and apolipoprotein concentrations and apo E genotypes were determined. We observed a greater effect of the apo E polymorphism on total cholesterol (TC), LDL-cholesterol (LDL-C) and especially apo B levels in children with birth weight in the lower tertile compared with those with birth weights in higher tertiles. Taking the epsilon3 allele homozygosity as reference, in boys with birth weights in the low tertile the overall lowering effect of the epsilon2 allele on TC, LDL-C and apo B was greater (10.5% (p < 0.01), 20.2% (p < 0.01) and 18.8% (p < 0.01), respectively) than in those in the highest tertile (5.6% on TC, 10.3% on LDL-C and 12.6% (p < 0.01) on apo B). A similar trend in this effect between tertiles of birth weight was also observed in girls. For both sexes, linear regression analysis demonstrates a positive and significant interaction between birth weight and epsilon2, which may explain the fact that the decrease in TC, LDL-C and apo B associated with the epsilon2 allele is more marked the lower the birth weight. Taking into account the prevalence of apo E polymorphism, and that appears to be the main genetic factor affecting plasma lipids, the interaction of apo E genotype and birth weight could be an important determinant of TC, LDL-C and apo B levels, and, as a consequence, of atherosclerosis.