Data from 1668 men (316 cardiovascular disease events) from the Framingham Offspring Study was reanalysed, specifically examining APOE:smoking interactions. Overall hazard ratio (HR) for smoking was 1.95 (1.52, 2.50) compared to non-smokers. Using epsilon3/3 as a referent group, in non-smokers HRs for epsilon2 carriers (epsilon2+; 1.04 (0.61, 1.76) and epsilon4 carriers (epsilon4+; 1.04 (0.70, 1.54) showed no major risk increase. In smokers, HRs were 1.96 (1.26, 2.78) in epsilon3epsilon3 men, 3.46 (2.14, 5.60; p = 0.09 for interaction) in epsilon2+ and 3.81 (2.49, 5.84; p = 0.01 for interaction), with a significant interaction between daily cigarette consumption and APOE genotype on risk (p = 0.03). The potential mechanism for this APOEepsilon4:smoking interaction was examined in a second study of 728 Caucasian patients with diabetes, where markers of reactive oxygen species were available. APOE genotype was not associated with plasma OX-LDL or total antioxidant status (TAOS) in non-smokers. However, in smokers epsilon4+ had 26.7% higher plasma OX-LDL than other genotypes (APOE:smoking interaction p = 0.04), while epsilon2+ had 28.4% higher plasma TAOS than epsilon3epsilon3 and epsilon4+ combined (APOE:smoking interaction p = 0.026). Although direct extrapolation needs to be considered with caution, these results identify that the cardiovascular disease risk-raising effect of epsilon4+ is confined to smokers, and a feasible mechanism is presented by the reduced antioxidant capacity/increased OX-LDL of apoE4.