Background: Type-2 diabetes mellitus (T2DM) increases the risk of breast cancer among postmenopausal women. Metformin has demonstrated a chemoprotective effect in breast cancer, however its role in HR+/HER2- breast cancer (HR+/HER2- BC), the most common subtype, has not been studied among older women with T2DM in the United States. This study evaluated if increased exposure to metformin is associated with a reduced risk of HR+/HER2- BC among postmenopausal women with T2DM. Methods: A case-control study was performed using the Surveillance, Epidemiology, and End Results (SEER)-Medicare data (2008-2015). Those diagnosed with HR+/HER2- BC as their first/only cancer after incident T2DM diagnosis were cases. The event date was the date of HR+/HER2- BC diagnosis in cases, and randomly assigned to non-cancer T2DM controls based on the distribution in cases. Cases were matched to up to 4 controls each using incidence density sampling with replacement. Metformin exposures were defined as cumulative dose, average intensity and adherence, measured during the 1-year lookback period prior to the event date. Dose (mg) was categorized as: 0, 0-30,000, 30,001-136,000, 136,001-293,000, and > 293,000. Average intensity per day (mg/day) was categorized as: 0, 1-500, and > 500. To evaluate adherence, those without metformin claims during the lookback period were excluded. Adherence measures were: binary proportion of days covered (PDC) (≥0.80, < 0.80) and adherence trajectories. Group based trajectory modeling was used to identify trajectories (adherent, slow decline, rapid decline, and early discontinuation). The Anderson Behavioral Model was used to guide selection of covariables: demographic and clinical variables (diabetes severity, metabolic syndrome, comedications, and health status). Conditional logistic regression was used to evaluate the association between exposure to metformin and the risk of HR+/HER2- BC. Results: The main cohort included 690 cases and 2747 controls. A decremental reduction in odds of HR+/HER2- BC in the highest cumulative dose (OR = 0.72, 95% CI: 0.55-0.95; OR = 0.60, 95% CI: 0.42-0.85) and intensity (OR = 0.61, 95% CI:0.46-0.82) categories of metformin was observed compared to the no-metformin group. Those non-adherent to metformin had 45% (OR = 1.45, 95% CI: 1.08-1.94) increased odds of HR+/HER2- BC compared to those adherent. The risk of HR+/HER2- BC in the adherent (OR = 0.67, 95% CI: 0.39-1.14), slow decline (OR = 0.75, 95% CI: 0.43-1.32) and rapid decline (OR = 0.73, 95% CI: 0.41-1.31) trajectories was not statistically significant compared to the early discontinuation trajectory. Conclusions: This retrospective study based on SEER-Medicare found an association between high dose and intensity of metformin use with reduced odds of incidence of HR+/HER2- BC among postmenopausal women with T2DM. Adherence to metformin also showed protective effect against HR+/HER2- BC.