A common assumption underlying most genetic studies is that individuals with different genotypes respond similarly to exposure to internal (epigenetic and background genotype effects) and external (ecological) environments. Here we evaluate whether this assumption is true in individuals with different genotypes of the gene coding for the apolipoprotein E (Apo E) molecule, an important determinant of the metabolic fate of plasma lipids and lipoproteins. We addressed whether the utility of known risk factors of coronary heart disease (CHD) in the prediction of CHD death in a 5-year follow-up is the same for the two most common Apo E genotypes, epsilon3/3 and epsilon4/3, in two cohorts of elderly Finnish men (age at baseline: 65-84 years), one in Eastern and the other in Southwestern Finland. The CHD mortality rate was higher in the epsilon4/3 than in the epsilon3/3 genotype in both cohorts (11.1 versus 7.8%, Pr = 0.281 in the Eastern cohort and 19.6 versus 8.2%, Pr = 0.002 in the Southwestern cohort). In the Eastern cohort, serum high density lipoprotein (HDL) cholesterol level was identified as a strong predictor of CHD death in the epsilon3/3 genotype (beta = -2.155, Pr = 0.019). In the Southwestern cohort, age (beta = 0.139, Pr = 0.006), body mass index (BMI) (beta = 0.149, Pr = 0.016), and serum total cholesterol level (beta = 0.453, Pr = 0.051) were identified as strong predictors in the epsilon3/3 genotype, as were smoking (beta = 0.236, Pr = 0.008) and BMI (beta = -0.124, Pr = 0.057) in the epsilon4/3 genotype. The latter observation indicates that in Southwestern Finland the probability of CHD death decreases with increasing BMI in elderly men with the epsilon4/3 genotype, while in their counterparts with the epsilon3/3 genotype the risk increases with increasing BMI. This difference was statistically significant (Pr = 0.002). These observations clearly argue against the assumption that individuals with different genotypes respond similarly to exposures to internal and/or external environments. These observations are consistent with a complex pathobiology of CHD involving biochemical and physiological agents that are under the influence of interactions between genetic and environmental factors. Information about these interactions is necessary for developing a more precise risk assessment and ultimately to improve public health and clinical strategies to prevent this devastating disease both at the individual and population levels.