Menopausal estrogen plus progestin therapy is associated with both increased incidence of breast tenderness and increased risk of breast cancer. This study analyzed data from participants of the Women's Health Initiative Estrogen plus Progestin Clinical Trial, a randomized trial of daily conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, or placebo in postmenopausal women. Breast tenderness was reported on questionnaires at baseline and at 12 months, and breast cancer incidence was recorded for an average of 5.6 years. Among the women who were assigned to active treatment, those who reported the new onset of breast tenderness (NOBT) at the 12-month follow-up visit had approximately a 1.5-fold increased risk of breast cancer compared with women who did not have NOBT at the 12-month follow-up visit. The authors conclude that NOBT during the use of conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, may identify women at elevated breast cancer risk.