Myeloperoxidase (MPO) is an oxidative enzyme present in phagocytes and atherosclerotic lesions. The MPO gene has a promoter polymorphism -463G/A, which leads to high (GG) and low expression (AG, AA) genotypes. We investigated the effect of long-term hormone replacement therapy (HRT) on the progression of atherosclerosis in a 5-yr follow-up study of postmenopausal women with different MPO genotypes. Eighty-seven nonsmoking postmenopausal women, aged 45-71 yr, were divided into three groups based on the use of HRT. The HRT-EVP group (n = 25) used sequential estradiol valerate plus progestin, the HRT-EV group used estradiol valerate alone (n = 32), and the control group (n = 30) used no HRT. The atherosclerosis severity score (ASC) for abdominal aorta and carotid arteries was determined by ultrasonography, and the MPO genotype was analyzed. In subjects with the GG genotype, the progression of ASC was significantly faster in the control group than in the HRT group (genotype by time interaction, P = 0.042), whereas in A allele carriers there were no significant differences in ASC progression between control and HRT. The effects of HRT on atherosclerosis progression in subjects with the GG genotype seem to be especially beneficial compared with controls with the same genotype but without HRT. These results may help us understand in greater detail the benefit and possible risk of HRT in atherosclerotic diseases.