BACKGROUND: Women with breast cancer are living longer, including those with risk factors such as having HER2+ tumors or diagnosed at later stages, but a dearth of information exists on patients’ outcomes beyond clinical trials. Thus, we aimed to describe breast-cancer specific mortality risk for women with HER2+ disease in a large community health plan. METHODS: We assembled a cohort of 3777 adult women (>18 years) with HER2+ breast cancer (AJCC TNM Stages I-IV) from a large California health plan, Kaiser Permanente Southern California, from 2009-2017 and followed them through December 2018. Subjects were identified from the health plan’s NCI-SEER affiliated tumor registry. All data elements were captured from the tumor registry and the electronic health records. ER, PR, and HER2 status were assessed by immunohistochemical or FISH techniques. Dates and causes of death were extracted from the inpatient records and state and national death databases. We computed breast cancer-specific mortality rates by exposure to trastuzumab, and by ER, PR, and tumor size. We followed women from the index date up to the date of death or end of study at December 31, 2018, whichever occurred first. Multivariable Cox proportional hazards regression was used to estimated adjusted hazard ratios (HR) and corresponding 95% confidence intervals. RESULTS: Of the 3777 women, the median age at diagnosis was 57 years (range: 22-99 years). The cohort was diverse and included 47% Whites; 12% African American/Blacks; 16% Asian/Pacific Islanders; 24% Hispanics; and 1% of other/mixed backgrounds. Roughly 67% (N=2464) were ER+ and/or PR+. A total of 3170 women (84%) received trastuzumab; N=112 (3%) other chemotherapy only; and N=495 (13%) neither (the majority [85%] had early stage I-II disease). The risk of breast cancer-specific death was 9.3% (351/3777) during a median follow-up of 4.4 years (maximum 10 years). Breast cancer mortality rate was markedly lower in those with trastuzumab (18.32/1,000 PY) therapy than those who did not receive trastuzumab (27.66/1,000 PY), corresponding to a 44% reduced risk (adj HR=0.56, 95% CI: 0.40-0.76) among those who received trastuzumab. Breast cancer mortality rates were higher in women with greater stage; ER-; PR-; tumors >2 cm and with positive lymph nodes. Compared to women diagnosed at Stage I, those with Stage II-III disease were 2.77 times (adj HR=2.77, 95% CI: 1.87-4.10) more likely to die of breast cancer, and this risk was even higher in those diagnosed at Stage IV (adj HR=11.11, 95% CI: 7.02-17.60), after accounting for trastuzumab use; diagnosis age and year; race/ethnicity; geocoded income; ER and PR status; surgery type; other adjuvant therapy (endocrine, radiation, chemotherapy); lymph node status; histology, BMI, Charlson Comorbidity Index. The adjusted breast cancer mortality risk was 37% greater (adj HR=1.37, 95% CI: 0.99-1.90) in those with ER- disease versus ER+, but the result was of borderline statistical significance. In those with tumors>2cm, breast cancer mortality risk was almost 90% greater (adj HR=0.67, 95% CI: 0.49-0.91) versus those with smaller tumors2 cm) and positive lymph nodes, even after accounting for trastuzumab use. Citation Format: Reina Haque, LieHong Chen, Karen W. Kwan, Nina Oestreicher, Deepa Lalla. Breast cancer mortality in women with Her2+ disease treated in a large integrated healthcare system [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-22.