Abstract Body: Introduction: Stroke is a common complication of infective endocarditis (IE), affecting 16–25% of cases, and can be the initial or sole manifestation of the condition. This study aims to analyze annual mortality trends and demographic factors related to stroke in IE patients in the U.S. and Texas from 1999 to 2020, to guide public health initiatives and enhance prevention strategies. Methods: The data was analyzed from the CDC's WONDER database from 1999 to 2020, focusing on stroke and IE-related mortality (ICD-10 Code I64.0 “Stroke” & Code I33.0 “IE”) in adults aged ≥65 years, annual percent changes (APCs) in age-adjusted mortality rates (AAMRs) with 95% confidence intervals across various demographic (sex, race/ethnicity, age) subgroups was calculated. Results: The AAMR for stroke-related mortality in IE cases reduced in the US from an adjusted rate (AR) 448.7 in 1999 to 171.6 in 2018 (APC: -8.09%; 95% CI: -9.00% to -6.81%) and then it increased to 183.5 in 2020 (APC: 3.07%; 95% CI: 1.22% to 4.69%). In Texas, AAMR for stroke-associated IE-related mortality overall decreased from AR 485.7 in 1999 to 176.2 in 2020 (APC: -5.23%; 95% CI: -5.50% to -4.96%). Males had higher consistently higher AAMRs than females (196.4 vs. 172). The AAMR in the US men decreased from 468.6 in 1999 to 176.7 in 2018(APC: -7.55%; 95% CI: -8.51% to -6.21%), then it increased to 196.4 in 2020(APC: 4.99%; 95% CI: 2.93% to 6.81%). The AAMR in the US women decreased from 431.5 in 1999 to 165.6 in 2018(APC: -8.25%; 95% CI: -9.15% to -6.97%) after which it increased to 172 in 2020(APC: 1.48%; 95% CI: -0.31% to 3.06 %). The non-Hispanic (NH) Black or African American (AA) has the greatest AAMR (278.7), followed by the NH White with an AAMR (179) and the NH American Indian or Alaska Native population with an AAMR (165.4). The low-risk populations were the Hispanic or Latino (143.6) and the NH Asian or Pacific Islander (135.2). AAMR also varied by region (overall AAMR: Midwest: 200.8; South: 193.9; Northeast: 166.2; West: 162.8) and non-metropolitan areas had higher AAMR (non-core areas: 233.4; micropolitan areas: 224.5) than metropolitan areas (large fringe metro areas: 170.5; large central metropolitan areas:160.4). Conclusions: The stroke-related mortality in infective endocarditis cases has overall risen in the United States than in Texas over the past two decades, specifically men and (NH) Black or AA, (NH) White and (NH) American Indian or Alaska Native are at high risk.