The increased risk of developing breast cancer, mostly estrogens receptor positive, particularly with the combination of estrogens and progestin, has been associated with an increased expression of estrogens receptors in the healthy breast tissue, thus leading to an enhanced sensitivity to the estrogens signal. Moreover, reproductive factors such as early menarche and delayed pregnancy are also associated with a higher risk of estrogens receptor (ER) positive breast cancer. Thus, the addition of a SERM may reduce the hormone growth-promoting effect on the breast gland. Tamoxifen has been investigated in four large cooperative phase III trials for breast cancer prevention in at-risk women. While the preliminary results of the Italian Tamoxifen Prevention Study in hysterectomized women showed no difference between arms, a recent update after 7 years of follow-up suggests that the combination of HRT and tamoxifen has a favorable effect and might even be synergistic. At a mean observation time of 81 months, a 25% reduction of breast cancer was noted in the tamoxifen arm compared with placebo (45 versus 34 events, Hazard Ratio, HR= 0.75, 95% CI, 0.48-1.18). While there is no difference in the subset of women who never took HRT before or during the trial (HR=1.01, 95% CI, 0.60-1.70), women, who at some point before or during the study, had ever taken HRT (n=1584) had fewer breast cancers in the tamoxifen arm (6 on tamoxifen versus 17 on placebo, HR=0.35, 95% CI, 0.14-0.89). Among the women continuously on HRT during the trial (n= 754), breast cancer events were 3 for women on tamoxifen versus 11 for those on placebo, respectively (HR=0.30, 95% CI, 0.08-1.06). Notably, 76.9% of HRT users received transdermal unopposed ERT and further 6.5% took transdermal ERT combined with progestins. Importantly, recent result from the IBIS I trial indicate that there is no evidence that HRT use affects the tamoxifen benefit. Recent studies suggest that the standard dose of tamoxifen may be reduced to one quarter (5 mg day) without significant loss of its beneficial effects on circulating biomarkers, mostly reflecting cardiovascular risk. Moreover, the efficacy of doses as low as one twentieth of the standard 20 mg/day dose on breast cancer cell proliferation has been recently shown. Since the endometrial effect of tamoxifen is dependent on treatment duration and dose, a dose reduction might reduce the risk of endometrial malignancies, while retaining its preventive efficacy. On the other hand, the addition of HRT containing progestins could further minimize the risk of endometrial cancer associated with tamoxifen. Moreover, estrogen should reduce the incidence of vasomotor and uro-genital symptoms, which are a major reason for tamoxifen withdrawal in prevention studies. In the NSABP trial, women aged 50 or younger demonstrated no significantly increased incidence of severe adverse events, including endometrial cancer and, even more importantly, venous thromboembolic events (VTE). One possible explanation for the lack of severe toxicity in premenopausal women is the concomitant presence of adequate circulating estrogens levels which prevent tamoxifen from acting as an estrogens agonist on these target tissues. Notably, in the IBIS I trial, no significant excess of endometrial cancer and VTE was noted in the women on HRT who were allocated to tamoxifen compared to placebo.