Once tamoxifen had been shown to reduce the risk of cancer reappearing after breast cancer surgery (in women with estrogen receptor-positive cancers), the question arose whether tamoxifen might also be helpful in preventing breast cancer in women at high risk of developing the disease.

The rationale for using tamoxifen to try to prevent breast cancer is similar to the rationale for using tamoxifen in breast cancer treatment. Estrogen-induced cycles of breast cell proliferation increase a woman's risk of developing breast cancer. Therefore, using tamoxifen to block the action of estrogen in the breast in healthy women might be expected to decrease a woman's chances of developing cancer in the future.

In 1992, the National Cancer Institute opened a study involving more than 13,000 healthy women considered to be at high risk for breast cancer based on their family or medical history. Half the women were given tamoxifen, while the other half were given a placebo. After 5 years, the group receiving tamoxifen had a lower rate of breast cancer.