Osteoarthritis (OA) remains a major epidemiological problem worldwide. The lack of established chondroprotective agents limits the clinical management of this disease to relief of symptoms, such as pain and joint stiffness. The marked increase in the prevalence and incidence of OA among women after the menopause draws attention to the possible contribution of estrogen deficiency to acceleration of cartilage degradation. Hormone replacement therapy (HRT) seems to counter the adverse influence of ovariectomy on the progression of joint lesions in various animal models, including nonhuman primates. Although decreases in the risk of OA associated with long-term HRT were repeatedly observed in large-scale epidemiological studies, the chondroprotective potential of this therapeutic option has received modest recognition among healthcare professionals. The overall diversity of results hampering our ability to draw conclusions at the present time arises from the diversity of methodological approaches and selected outcome measures of OA. Randomized clinical trials using state-of-the-art methodology, such as high-resolution magnetic resonance imaging that allows direct visualization and morphometric characterization of articular cartilage and biochemical markers of cartilage turnover that can provide early indication of therapeutic effects, are awaited to obtain evidence-based answers to the utility of estrogen in the prevention of OA