Atherosclerotic changes associated with long-term hormone replacement therapy (HRT) were evaluated in 20 postmenopausal women (mean age, 62.8 +/- 6.1 years). The duration of hormone therapy was 10.1 +/- 3.4 (SD) years. For 9 women the HRT was sequential estradiol valerate plus levonorgestrel, for 6 women estradiol valerate plus medroxyprogesterone acetate and for 5 women estradiol valerate alone. Examinations consisted of histologic and biochemical studies of the uterine artery and ultrasonographic examinations of carotid arteries, aorta and iliac arteries. The findings were compared with those in 20 postmenopausal women of similar age and with similar body mass indexes who had never received HRT. Additionally, the same examinations were performed on 10 premenopausal women (48.3 +/- 4.6 years). The uterine artery was histologically normal in all the premenopausal women studied. Among the postmenopausal women without HRT, a histologically normal uterine artery was found in 5% and in women on HRT in 55% of cases (P < .01). In medicolegal autopsies, atherosclerosis in the uterine artery correlated significantly with atherosclerosis in the coronary artery and aorta. The free cholesterol content of the intima media in premenopausal women was lower than in postmenopausal women without HRT. The percentage of linoleic acid in the intima was significantly lower and that of docosapentaenoic acid significantly higher in premenopausal women and in postmenopausal women on HRT than in postmenopausal women without HRT. In the ultrasonographic examination atherosclerosis in the carotid artery was less common in premenopausal women and in women on HRT than in postmenopausal women without HRT. In this material, histologic, biochemical and radiologic studies showed that HRT may be protective against atherosclerosis.