Abstract Body: Introduction: Hypertension and liver diseases both increase mortality, but their combined effect is unknown. Mortality from liver disease in the U.S. has increased for unknown reasons. Identifying demographic and regional inequalities may improve risk stratification and public health.Hypothesis: Hypertension affects liver disease mortality differently by sex, race/ethnicity, age, urbanization, and geography. Methods: We performed a retrospective analysis using mortality data from the 1999–2020 CDC WONDER Multiple Cause of Death database.ICD-10 codes identified liver disease as the underlying cause of death (B18.0, B18.2, C22.0, C22.1, C22.7, K70.0–K70.4, K70.9, K72.0–K72.1, K74.0, K74.3–K74.6, K76.0, and K76.6) and hypertensive (I10–I15) and cardiovascular-related conditions as contributing causes. We retrieved year-by-year AAMRs per 100,000 population and mortality. Adults 25 and older were divided into 10-year age groups. Rates were based on the 2000 U.S. standard population and 2001–2009 default intercensal population estimates. Zero- or suppressed-count records were removed. Results: Between 1999 and 2020, a total of 186,669 liver-related deaths were reported in the United States. The AAMR increased by 93.5%, rising from 3.02 per 100,000 in 1999 to 5.85 in 2020. In 1999, non-Hispanic American Indian/Alaska Natives had the highest AAMR (5.99), while NH Asian/Pacific Islanders had the lowest (2.31). This trend persisted into 2020, with NH American Indian/Alaska Natives exhibiting the highest AAMR (13.09) and NH Asian/Pacific Islanders the lowest (3.1). The greatest overall increase was also noted among NH American Indian/Alaska Natives (AAPC: 4.17%; 95% CI: 2.34–6.03). Females experienced a higher increase in liver-related mortality compared to males (AAPC: 3.65%; 95% CI: 3.10–4.30 and 2.16%; 95% CI: 3.36–9.14, respectively). Regionally, the South experienced the most significant increase (AAPC: 3.51%; 95% CI: 2.68–4.33), whereas the Northeast showed the least (AAPC: 1.42%; 95% CI: 0.59–2.25). When stratified by urbanization, rural areas had a faster rise than urban areas (AAPC: 4.62% vs. 2.80%). Mortality in the 25–34 age group increased significantly (4.82%) between 1999 and 2020. Conclusion: Rural, female, and NH American Indian/Alaska Native mortality from coexisting hypertension and liver illness is rising despite therapeutic advances. These findings highlight the need for vulnerable population-focused combined cardiovascular and liver disease care.