BACKGROUND: The frequency of migraine headache changes at various times of a woman's reproductive cycle. Menarche, menses, pregnancy, and perimenopause may carry a different migraine risk conceivably because of fluctuating estrogen levels, and in general, migraine frequency is associated with falling estrogen levels. Given the strong relationship between endogenous estrogen levels and breast cancer risk, migraine sufferers may experience a reduced risk of breast cancer. METHODS: We combined data from two population-based case-control studies to examine the relationship between migraine and risk of postmenopausal invasive breast cancer among 1,199 ductal carcinoma cases, 739 lobular carcinoma cases, and 1,474 controls 55 to 79 years of age. Polytomous logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: Women who reported a clinical diagnosis of migraine had reduced risks of ductal carcinoma (OR, 0.67; 95% CI, 0.54-0.82) and lobular carcinoma (OR, 0.68; 95% CI, 0.52-0.90). These associations were primarily limited to hormone receptor-positive tumors as migraine was associated with a 0.65-fold (95% CI, 0.51-0.83) reduced risk of estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+) ductal carcinoma. The reductions in risk observed were seen among migraine sufferers who did and did not use prescription medications for their migraines. CONCLUSIONS: These data suggest that a history of migraine is associated with a decreased risk of breast cancer, particularly among ER+/PR+ ductal and lobular carcinomas. Because this is the first study to address an association between migraine history and breast cancer risk, additional studies are needed to confirm this finding.