Abstract Background: The prognosis of early-stage, hormone receptor-positive breast cancer is excellent with 5-year overall survival rates greater than 90%. In the context of excellent survival, it is important to quantify the long-term comorbidities associated with endocrine therapy. Methods: Eligible patients were women diagnosed with stages 1-3, hormone receptor-positive and Her2-negative breast cancer from January 1999 to December 2016 and treated at one or more of two healthcare systems in the San Francisco Bay Area (Stanford University or the community-based Palo Alto Medical Foundation, N=3,044). Duration of therapy with aromatase inhibitors and/or tamoxifen was ascertained. Long-term comorbidities analyzed were congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cerebrovascular accidents (CVA), dementia, depression/anxiety, diabetes mellitus (DM), peptic ulcer disease (PUD), hyperlipidemia (HLD), myocardial infarction (MI), non-alcoholic steatohepatitis (NASH), osteonecrosis of the jaw, osteoporosis, peripheral vascular disease (PVD), and venous thrombotic events (VTE). Pre-existing comorbidities were defined as those diagnosed any time up to 1 year after breast cancer diagnosis. Incident comorbidities that developed on or after endocrine therapy were defined as those diagnosed any time after 1 year following breast cancer diagnosis. Results: The median patient age was 58.1 years. Patients were 67.8% non-Hispanic white, 22.1% Asian, 7.6% Hispanic, 1.7% non-Hispanic Black, and 0.8% other. Most (69.6%) had private insurance. For endocrine therapy, almost half (48.3%) used aromatase inhibitors only (median duration 35.1 months), 20.6% used tamoxifen only (median duration 29.4 months), and the remainder used both aromatase inhibitors (AI) and tamoxifen (median duration of any endocrine therapy: 47.8 months). Comorbidity results are in the Table. Notable unadjusted hazard ratios for the association of incident comorbidities with tamoxifen (versus AI) use include: HLD 0.45 [95% confidence interval, CI 0.25-0.8]; MI 0.66 [CI 0.04-9.88]; CHF 1.23 [CI 0.29-5.1]; CVA 0.46 [CI 0.14-1.54]; depression/anxiety 0.89 [CI 0.45-1.76]; osteoporosis 0.37 [CI 0.23-0.59]; and DM 1.34 [CI 0.44-4.07]. Results of multivariable analysis will be presented, adjusting for comorbidities present before cancer diagnosis, age, race and insurance status. Conclusions: In a diverse, real-world cohort of breast cancer patients treated in two healthcare systems, incident HLD and osteoporosis were significantly less common with tamoxifen versus AI use, while other comorbidities did not vary with type of endocrine therapy. These results may inform clinical decision-making about endocrine therapy for early-stage, hormone receptor-positive breast cancer. Table. Comorbidities relative to timing of breast cancer diagnosisComorbidityPrevalence before cancer diagnosisIncidence after cancer diagnosisCongestive heart failure65 (2.1)70 (2.3)Chronic obstructive pulmonary disease348 (11.4)127 (4.2)Cerebrovascular accident83 (2.7)77 (2.5)Dementia15 (0.5)25 (0.8)Depression/Anxiety599 (19.7)245 (8)Diabetes239 (7.9)101 (3.3)Peptic ulcer disease36 (1.2)19 (0.6)Hyperlipidemia870 (28.6)363 (11.9)Myocardial infarction12 (0.4)18 (0.6)Non-alcoholic steatohepatitis40 (1.3)62 (2)Osteonecrosis of jawNA (NA)2 (0.1)Osteoporosis/Fracture791 (26)608 (20)Peripheral vascular disease22 (0.7)31 (1)Venous thrombotic event65 (2.1)74 (2.4) Citation Format: Tanya Gupta, Natasha Purington, Mina Liu, Summer Han, George Sledge, Lidia Schapira, Allison Kurian. Incident comorbidities in a diverse cohort of women treated for early-stage, hormone receptor-positive breast cancer [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 PS9-24.