Myeloperoxidase (MPO) is an enzyme that transforms low-density lipoprotein into atherogenic particles. The MPO gene has a promoter polymorphism at position -463, which affects gene transcription and leads to high- (G/G) and low-expression (A/A, A/G) genotypes. To determine if these genotypes are associated with the severity of atherosclerosis, we performed an autopsy study of 300 men aged 33 to 69 years (Helsinki Sudden Death Study). We examined the percentage area of fatty streaks and fibrotic, calcified, and complicated lesions using computer-assisted planimetry. The MPO genotypes were determined by PCR. There were significant interactions of MPO genotype with the mean area of fibrotic (p < 0.01) and calcified (p < 0.05) lesions in the abdominal aorta and in fibrotic lesions in the thoracic aorta (p = 0.003). In the abdominal aorta, men < 53 years with low-expression genotypes had on average a 38.6% larger area of fibrotic lesions and a 43.8% larger area of calcified lesions than did the subjects with the G/G genotype. This association weakened with advancing age. Among men < 53 years, the MPO genotype was an independent predictor of fibrotic (p = 0.037) and calcified (p = 0.001) lesion area in the abdominal aorta after adjustment for age, body mass index, diabetes, hypertension, and smoking. MPO gene variation may modify the extent of advanced atherosclerotic lesions in the human aorta in early middle age.