Background: Treatment patterns and clinical outcomes are unclear for MBC patients diagnosed with estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+) human epidermal growth factor 2 positive (HER2+) disease (i.e. triple positive). This study aimed to: 1) examine the utilization of first-line therapy among ER+/PR+/HER2+ MBC patients and 2) compare overall survival (OS) between the identified regimens. Methods: We analyzed triple positive MBC patients included in the National Cancer Database who were treated with endocrine therapy (ET) or chemotherapy (chemo) between 2010 and 2015. Kaplan-Meier method was used to estimate distributions of OS, which were compared among patient cohorts using the log-rank test. Results: A total of 6,234 patients were included in the analysis; of these, 3770 (60%) received ET and 2464 (40%) received chemo. Of those with complete survival data, there was no difference in median OS between patients treated with chemo vs. ET; however, those who received anti-HER2 therapy had significantly better OS than those who did not (median OS 49.4 vs. 41.0 months, p < 0.0001). Median OS stratified by ET or chemo with and without anti-HER2 further supported these findings, revealing the addition of anit-HER2 therapy to chemotherapy and ET resulted in superior median OS (Table). Conclusions: This is the first study to evaluate treatment utilization and OS among real-world triple positive MBC patients treated with ET or chemo. Our results suggest the majority of patients in the United States are treated with first-line ET; furthermore, the reported OS outcomes support the consideration of ET plus anti-HER2 therapy as a first-line treatment option for ER+/PR+/HER2+ MBC. Prospective trials evaluating de-escalation of systemic therapy in this subgroup of patients and future research to identify biomarkers to determine which patients can avoid chemotherapy are warranted.