Description: Aims The genetic polymorphism of apolipoprotein E ( APOE ) has been suggested to modify the effect of smoking on the development of coronary artery disease (CAD) in apparently healthy persons. The interaction of these factors in persons undergoing coronary angiography is not known. Methods and results We analysed the association between the APOE-genotype , smoking, angiographic CAD, and mortality in 3263 participants of the LUdwigshafen RIsk and Cardiovascular Health study. APOE-genotype s were associated with CAD [22 or 23: odds ratio (OR) 0.56, 95% confidence interval (CI) 0.43–0.71; 24 or 34 or 44: OR 1.10, 95% CI 0.89–1.37 compared with 33] and moderately with cardiovascular mortality [22 or 23: hazard ratio (HR) 0.71, 95% CI 0.51–0.99; 33: HR 0.92, 95% CI 0.75–1.14 compared with 24 or 34 or 44]. HRs for total mortality were 1.39 (95% CI 0.39–0.1.67), 2.29 (95% CI 1.85–2.83), 2.07 (95% CI 1.64–2.62), and 2.95 (95% CI 2.10–4.17) in ex-smokers, current smokers, current smokers without, or current smokers with one 4 allele, respectively, compared with never-smokers. Carrying 4 increased mortality in current, but not in ex-smokers (HR 1.66, 95% CI 1.04–2.64 for interaction). These findings applied to cardiovascular mortality, were robust against adjustment for cardiovascular risk factors, and consistent across subgroups. No interaction of smoking and 4 was seen regarding non-cardiovascular mortality. Smokers with 4 had reduced average low-density lipoprotein (LDL) diameters, elevated oxidized LDL, and lipoprotein-associated phospholipase A2. Conclusion In persons undergoing coronary angiography, there is a significant interaction between APOE-genotype and smoking. The presence of the 4 allele in current smokers increases cardiovascular and all-cause mortality.