Purpose The combination of chemotherapy and trastuzumab is the standard of care for adjuvant treatment of human epidermal growth factor receptor 2-positive breast cancer. Two regimens have been widely adopted in the United States: doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab (ACTH) and docetaxel, carboplatin, and trastuzumab (TCH). No head-to-head comparison of these regimens has been conducted in a clinical trial, and existing trial data have limited generalizability to older patients. Methods We used SEER-Medicare data from 2005 to 2013 to compare outcomes of ACTH versus TCH among patients age older than 65 years. Propensity score matching was used to balance cohort characteristics between treatment arms. Outcomes included toxicity-related hospitalization, survival, and trastuzumab completion. Data from 1,077 patients receiving ACTH or TCH were analyzed, and the propensity-matched subsample included 416 women. Results There was a significant shift toward TCH over time, with 88% of patients receiving ACTH in 2005 compared with 15% by 2011. Among propensity score-matched patients, we found no difference between regimens in health care use overall or for chemotherapy-related adverse events (ACTH, 34% v TCH, 36.5%; P = .46). Patients receiving TCH were significantly more likely to complete trastuzumab (89% v 77%; P = .001). There was no difference in 5-year breast cancer-specific survival (ACTH, 92% v TCH, 96%; hazard ratio, 2.08; 95% CI, 0.90 to 4.82) or overall survival. Conclusion Among a matched sample of older patients, ACTH compared with TCH was not associated with a higher rate of serious adverse events or hospitalizations, but it was associated with less completion of adjuvant trastuzumab. We did not detect a difference in 5-year survival outcomes for ACTH compared with TCH. In the context of limited evidence in older patients, selection between these two regimens on the basis of concerns about differential toxicity or efficacy may not be appropriate.