Several data implicate the immune system in bone lost after estrogen deficiency, however, some of the effects on the immune system of estrogen deficiency or of estrogen receptor (ER) modulation are not well established. In this study, the effect of ER agonists on the immune system in ovariectomized mice is analyzed. Mice were ovariectomized and were administered 178-estradiol (E2), raloxifene (RAL) or genistein (GEN). The effect of a 4-week treatment on bone turnover and on several parameters that reflect the status of the immune system was studied. Results show that ovariectomy provoked both uterine atrophy and thymic hypertrophy. Although RAL corrected thymic hypertrophy, only E2 corrected both. Ovariectomized mice showed increased levels of serum calcium and cathepsin K gene expression and decreased levels of serum alkaline phosphatase (ALP) activity, which suggests that there is a persistent alteration in bone metabolism. Moreover, ovariectomy increased B-cells and CD25+ cells, and decreased the percentages of T-cells and Cbfal gene expression in bone marrow (BM). All ER agonists corrected, although to different degrees, changes induced by the ovariectomy. Furthermore, results showed that it is essential to adjust ER agonist doses to avoid immunosuppression, since all ER agonists decreased BM T-cell levels.Osteoporosis is a major public health problem which is characterized by low bone mass and an increased risk of fracture. It is known that estrogen deficiency is a well-established cause of osteoporosis and a major risk factor for bone loss and fractures, whereas hormone replacement therapy (HRT) prevents, or even reverses, bone loss and reduces fracture risk (l). However, the recent Women's Health Initiative clinical study (2) shows an increase in the index of cancer appearance and cardiovascular risk in postmenopausal women taking HRT. Therefore, attention has been centered on other therapeutic possibilities with lesser side-effects. Among the products that exert their bone function through estrogen receptors (ERs), it is necessary to underscore the Selective Estrogen Receptor Modulators (SERMs) and phytoestrogens.