Abstract Purpose: Breast cancer (BC) mortality rates have been declining over time; however, the decline is not consistent across racial/ethnic groups. Prior studies suggest that comorbidities, including hypertension, are associated with treatment delays, increased hospitalizations, and higher mortality in BC patients, but these studies have been limited to women with non-metastatic BC. The influence of common comorbidities on BC mortality, and their contribution to survival disparities in patients with metastatic BC (mBC), remains unknown. We examined the influence of hypertension on all-cause mortality, and if this disparity can be mitigated by better pharmacologic management of hypertension in a diverse cohort. Methods: This longitudinal cohort included 1,332 women diagnosed with de novo mBC between 2008-2020 at Kaiser Permanente Southern California (KPSC). We extracted data on cancer-related variables, sociodemographic, and clinical variables from KPSC’s cancer registry, pharmacy dispensings, and electronic health records. Deaths were identified from in-patient and national death databases. We followed patients electronically from mBC diagnosis until patients died or reached study’s end (12/31/2021), whichever occurred first. We computed person-year rates of all-cause mortality by use of antihypertensive medication (monotherapy [one drug class] or polytherapy [multiple drug classes]). Multivariable Cox regression with time-varying antihypertensive drug use status was used to estimate the association [HR, 95% CI] between overall mortality and use of antihypertensives. Results: The cohort consisted of 46.1% women of color. Overall, 48.4% patients had hypertension at mBC diagnosis, with Black patients (64.5%) having the highest prevalence, followed by White (46.3%), Hispanic (46.1%), and Asian/Pacific Islander (API) patients (42.7%). During follow-up, 52.8% were treated with antihypertensive medications (20.3% received monotherapy; 32.5% polytherapy). Overall mortality rates were lower in those treated with antihypertensive polytherapy (21.3/100 PY) vs. monotherapy (28.50/100 PY). Compared to monotherapy, the percent mortality rate reduction was greater in those treated with polytherapy, particularly in Black patients (35.7% reduction), followed by White (28.7%), Hispanic (15.9%) and API patients (7.60%) (P<0.05). After adjusting for age, SES, cancer treatments, other comorbidities and covariate medications, mortality risk was 44% lower (HR=0.56; 95%CI: 0.43-0.75) among those treated with polytherapy vs. monotherapy; this protection was even greater in Black women (HR=0.43; 0.19-0.97) and Hispanic women (HR=0.47; 0.24-0.95). Conclusion: In women with de novo mBC, hypertension was the most common comorbidity, and highest in Black women. All-cause mortality risk was lower among those treated with polytherapy vs. monotherapy for hypertension, with the greatest attenuation seen amongst Black and Hispanic women. Pharmacologic management of hypertension in women with mBC may potentially help extend life and mitigate mortality disparities. Citation Format: Reina Haque, Amrita Mukherjee, Lie Hong Chen, Tiffany Hogan, Moira Brady-Rogers, Zheng Gu, Ariel Silverman, Lauren P. Wallner. Influence of hypertension management on all-cause mortality in a multiethnic cohort of women with metastatic breast cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C128.