Hormone replacement therapy (HRT) in post-menopausal or ovariectomized women reduces mortality due to cardiovascular diseases, lowers morbidity due to osteoporosis and improves vasovagal symptoms. Long-term therapy, however, increase the risk of side-effects. HRT may decrease mammographic sensitivity, markedly increasing glandular density. Enlargement of pre-existing cysts and fibroadenomas has also been reported after HRT. The correlation between HRT and breast cancer is highly controversial. We examined 650 women: 550 of them (84.6%) received HRT (157 estrogens and 393 estrogens-progestins) and 100 (15.4%) refused treatment and were thus considered as a control group. All patients underwent mammography and DEXA before HRT and, during treatment, were followed-up yearly with mammography, often combined with US, and DEXA. Fisher's test was used for data analysis (confidence interval: 95%). The statistical analysis showed a significant difference between the HRT group and the control group only for the lumbar spine. Mammographic changes (Tab. II) were shown in 150 of 550 HRT patients. Increased breast density was the most frequent finding. Benign lesions arising de novo or increasing in size and/or number were observed in 41 of 150 patients (27.3%) in the HRT group, where 3 breast carcinomas were detected, versus 1 breast cancer only in the control group. HRT had a marked positive effect on bone mineral content (BMC) at 2 years' follow-up, but it remains debated if it reduces breast cancer risk. In conclusion, our results indicate that a yearly mammography is mandatory in long-term HRT subjects and US may be also needed in particularly dense breasts.