The Breast Cancer Prevention Trial (P-1: BCPT) of the National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized 13,388 women, > or = 35 years of age, at increased risk for breast cancer [> or = 1.66% by Gail model criteria or with a history of lobular carcinoma in situ (LCIS)] to 5 years of tamoxifen or placebo. A 49% reduction (P < 0.00001) in invasive breast cancers occurred, 175 with placebo versus 89 with tamoxifen, mainly among estrogen receptor (ER)-positive tumors (130 with placebo vs. 41 with tamoxifen). The major toxicities of tamoxifen were endometrial cancer (15 with placebo vs. 36 with tamoxifen) and thromboembolic disease, both predominantly in women who were > or = 50 years old. Ramifications emerging from the P-1 results regarding the efficacy and toxicities of preventive tamoxifen include the following: (1) Does tamoxifen induce more virulent breast cancers? (2) Does tamoxifen induce more virulent endometrial cancers? (3) Tamoxifen is especially efficacious in reducing breast cancer risk in LCIS (18 invasive breast cancers with placebo vs. 8 with tamoxifen group) and atypical ductal hyperplasia (AH) (23 invasive breast cancers with placebo vs. 3 with tamoxifen). (4) Does tamoxifen reduce breast cancer risk in women at increased risk due to genetic mutations? (5) How can we prevent tamoxifen-resistant breast cancers? (6) What do the BCPT results tell us about who should take preventive tamoxifen? In its ongoing effort to lower the incidence of breast cancer, the NSABP is now implementing its second breast cancer prevention trial, the Study of Tamoxifen and Raloxifene (STAR), which is comparing the two agents with regard to efficacy and toxicity.