The positive effects of hormonal replacement therapy (HRT) in protecting the cardiovascular system in women have been supported by several observational studies, while also being questioned by other randomized controlled trials. Today, it is unclear whether HRT plays a crucial role, or even whether there is any role at all, for this therapy in preventing or in lowering cardiovascular disease (CVD). In the present study, we have evaluated the effectiveness of long-term HRT in post-menopausal women on the incidence of cardiovascular events and arterial remodeling, as well as on some metabolic factors. Eighty-four post-menopausal women (mean age: 46.3 ± 5.2; age range: 42-66 yr) underwent HRT for 10.9 ± 1.2 yr (range: 8-12 yr). None of these subjects showed new cardiovascular events, and we found a reduction of the intima-media thickness (baseline: 1.39 ± 0.2, 1.35 ± 0.2, 1.31 ± 0.2 mm) and total cholesterol, LDL and antithrombin III levels were lower, while HDL and fibrinogen levels increased. The study highlights a number of positive effects both on vascular conditions and metabolic and coagulative markers that are usually considered as generic and crucial risk factors for CVD. The relatively low number of patients is perhaps a limitation of this study, however, the long-term period of followup should be considered an interesting and important factor. Furthermore, this study underlines the real-life clinical experience of a Menopause Center.