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Objective: Postmenopausal hormone use and risk of breast cancer by histopathology was examined in a large multi-centered population-based case–control study. Methods: Women younger than 75 years newly diagnosed with invasive breast cancer between 1988 and 1991 were identified from statewide tumour registries in Wisconsin, Massachusetts, New Hampshire, and Maine. Only postmenopausal women were included in this analysis. Breast cancer cases (lobular (n = 219), ductal, NOS (n = 2172), and specific ductal subtypes (n = 242)) were compared with randomly selected population controls (n = 3179) using adjusted multi-variable polytomous logistic regression to estimate odds ratios (OR) and 95% confidence intervals (95%CI) for each histology. Results: Lobular carcinoma was associated with recent (within 2 years) estrogen therapy (OR:1.8, 95%CI: 1.0–3.4) and recent use of combined estrogen-plus-progestin therapy (OR:3.6, 95%CI: 1.8–7.6). Risk of ductal carcinoma was not associated with recent use of either estrogen alone (OR: 0.9, 95%CI: 0.7–1.2) or combined therapy (OR:0.9, 95%CI: 0.6–1.3). No associations were found with ductal subtypes. Conclusions: The association between postmenopausal hormone use and risk of breast cancer may depend on histopathology. Of particular interest is the association between combined hormone therapy and increased risk of lobular carcinoma. This lesion is increasingly common but, nonetheless, comprises fewer than 10% of invasive breast cancers.