BACKGROUND: Data from large prospective studies are needed to fully characterize the impact of exogenous hormones on breast cancer incidence by type of hormone preparation and histology of the cancer. METHODS: In a prospective cohort of 67,754 postmenopausal women in the US, 1821 cases of invasive ductal cancer and 471 cases of invasive lobular or mixed lobular cancer occurred during 13 years of follow-up. The authors computed age-adjusted rates, as well as age-adjusted and multivariate-adjusted rate ratios (RR) for ductal and lobular breast cancer and for the use of estrogen only (E-only) and estrogen and progesterone (E + P) for current and former hormone users by duration of use and years since last use. RESULTS: Current use of E + P was associated with an increased risk of both ductal (RR of 1.75; 95% confidence interval [95% CI], 1.53-2.01) and lobular (RR of 2.12; 95% CI, 1.62-2.77) breast cancer. Risk increased within the first 2 to 3 years of use and attenuated 2 years after cessation. In contrast, current use of E-only was not associated with an overall increased risk of invasive ductal cancer. The only exceptions to this finding were in lean (body mass index <25) women and for ductal cancers diagnosed at the regional/distant stage, where in both cases the use of E-only was associated with an increased risk. E-only use was associated with a 50% increased risk of invasive lobular cancer after >or=10 years of use. CONCLUSIONS: Use of E + P is more detrimental to the breast than E-only use, in terms of both ductal and lobular cancer. The findings from the current study suggest a window of 2 to 3 years for the risks of E + P both to become apparent after initial use and to attenuate after cessation. (c) 2009 American Cancer Society.