Background: High-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplant (HSCT) has been used as part of the treatment of metastatic breast cancer. However, the evidence behind this approach continues to be controversial. We hypothesize that previous radiation therapy (RT) may increase the risk of cardiomyopathy and mortality in these patients. Methods: Patients who underwent HSCT after HDCT for breast cancer treatment during 1988-2012 were included. The patients that underwent HSCT for indications other than breast cancer were matched 1:2 based on age and gender. The data was analyzed using the cox proportional hazard model, looking at time-to-survival with adjustments made for cardiotoxic chemotherapeutics, histology of cancer, ER/PR status, EGFR mutation status, number of RT sessions, age, and functional status. Results: Sixty-six patients with metastatic breast cancer underwent HSCT. Patients with breast cancer were more likely to develop systolic heart failure (10% vs. 6.1%, p=0.002). There were 29 (43.9%) patients who underwent whole breast RT (WBRT). Prior WBRT was an independent predictor of developing post-transplant systolic heart failure (HR 3.77; 95% CI 1.29–10.75, p=0.007). The Kaplan–Meier curve shows a better survival for patients without a previous WBRT (Log rank p=0.009). Patients with prior WBRT were found to have decreased survival (HR 1.59; 95% CI 1.16–2.17, p=0.004). Conclusions: Patients with a history of WBRT who underwent HSCT were more likely to develop new onset systolic heart failure than patients without WBRT. This might be due to the effects of RT on the coronary arteries and the cardiac myocytes, leading to worse outcomes. Future studies are needed to evaluate outcomes of HSCT in patients with metastatic breast cancer without prior WBRT.