Rationale: The combination of chemotherapy and the monoclonal antibody trastuzumab is the standard of care for systemic adjuvant therapy of HER2-positive breast cancer, substantially improving patient outcomes. Two regimens have been widely adopted for use in the United States, adriamycin/cyclophosphamide/paclitaxel/trastuzumab (ACTH) and docetaxel/carboplatin/trastuzumab (TCH). While other options are available in the neoadjuvant and low-risk settings, ACTH or TCH remain standard of care for many women with early-stage HER2+ disease. No head-to-head comparison of these regimens has been conducted in a clinical trial, and the clinical trial data have limited generalizability due to the exclusion of older women and the low representation of minorities and those with significant co-morbidities. Research Objectives: We used SEER-Medicare data from 2005-2013 to conduct a comparative effectiveness study of ACTH vs TCH among patients over 65 receiving trastuzumab-based adjuvant chemotherapy. An intent-to-treat analytic design was applied and propensity score matching was used to account for selection bias and to balance cohort characteristics between treatment arms. Outcomes included toxicity-related hospitalization, survival, and regimen completion (receiving ≥ 270 days of trastuzumab). Toxicity was evaluated using inpatient and emergency room claims for chemotherapy-related adverse events in the first six months of therapy, as well as all-cause hospitalization over the same period. Data from 1077 patients with HER2+ disease were analyzed and the propensity-matched sub-sample included 416 women. Results: Over time there was a significant shift in regimen use between ACTH vs TCH, with 88% of patients in 2005 receiving ACTH compared to only 15% by 2011. Using the propensity score-matched patients, we found no difference between regimens in healthcare utilization for chemotherapy-related adverse events or all cause hospitalization. (RR=0.99, 95% CI 0.64-1.51) Patients receiving TCH were significantly more likely to complete trastuzumab (89% for TCH vs 77% for ACTH). There was no difference between regimens in five year breast cancer-specific survival or overall survival. Results of a sensitivity analysis limited to patients who completed trastuzumab were similar to the primary analysis. Conclusions: Among older women with HER2+ breast cancer receiving multi-agent regimens with similar levels of medical comorbidity, ACTH compared to TCH did not appear to be associated with a higher rate of serious adverse events or hospitalizations, but was associated with a lower rate of completion of adjuvant trastuzumab. Ability to evaluate cardiotoxicity in this claims-based analysis was limited. We did not detect a difference in five year survival outcomes for ACTH compared to TCH. In the context of limited evidence in older patients, there appears to be little difference between the two regimens in terms of either toxicity or efficacy. Citation Format: Reeder-Hayes KE, Meyer AM, Hinton SP, Ke M, Carey LA, Dusetzina SB. Comparative toxicity and effectiveness of trastuzumab combined with anthracycline versus platinum chemotherapy regimens for adjuvant therapy of HER2+ breast cancer in older women [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-13.