High-density lipoprotein-associated paraoxonase 1 (PON1) enzyme can retard the oxidation of lipids. The methionine for leucine substitution at position 55 (M/L55) of the PON1 protein is associated with lower (MM genotype) or higher (ML or LL genotype) expression of the gene affecting serum level of PON1. We studied the association of the PON1 M/L55 genotype with the extent of atherosclerosis in an autopsy series of Finnish males. Areas of the coronary arteries and the aorta covered with fatty streaks and fibrotic and complicated lesions were measured from a total of 700 cases. Carriers of the MM genotype (14.4% of subjects) had larger percentual areas of fatty streaks in their left anterior descending coronary artery (P=0.014) and right coronary artery (P=0.004), as well as in thoracic (P<0.001) and abdominal aorta (P=0.010) compared to carriers of the LL or ML genotype. A PON1 genotype-by-smoking interaction was observed on the area of fatty streaks in left anterior descending coronary artery (P=0.011) and right coronary artery (P=0.005); the association between fatty streaks and MM genotype was evident only among non-smokers, whereas in smokers this association was abolished. The areas of more advanced atherosclerotic lesions did not vary significantly between the genotype groups. These data suggest that the genetic variation of PON1 affects the formation of early atherosclerotic lesions and that the effect is modified by smoking.