<p>Cirrhosis and renal failure represent major global health conditions with high prevalence and mortality. Among cirrhotic patients, renal failure, particularly in the form of hepatorenal syndrome, has been identified as a major determinant of adverse outcomes and mortality. Given this well-established association, we aimed to evaluate mortality trends related to renal failure among adults with cirrhosis in the United States from 1999 to 2023. Mortality data were sourced from death certificates available through the CDC WONDER Multiple Cause of Death database for patients with renal failure with cirrhosis, from 1999 to 2023. AAMRs (age-adjusted mortality rates) were calculated, and standardized to 2000 U.S. population. APCs (annual percent changes) were derived through Joinpoint regression analysis. Data was stratified by multiple demographic and regional variables, including age group, sex, and urban-rural status. In total, 192,851 deaths were attributed to renal failure with coexisting liver cirrhosis from 1999 till 2023 in the US. The twenty-five year analysis revealed an overall rise in AAMR, from 2.5 in 1999 to 5.6 in 2023. Sex-stratified analyses showed consistently higher AAMRs among men than women across the study period. Racial and ethnic stratification demonstrated the highest age-adjusted mortality rates in the Hispanic or Latino population (AAMR, 5.6), while the lowest rates were observed in the NH Asian/Pacific Islander populations (AAMR, 2.0). Geographical analysis showed that the Western region and Texas accounted for the highest mortality burden, while metropolitan and nonmetropolitan areas were affected to a similar extent. These disparities across demographic and geographical variables underscore the importance of targeted interventions and strategic allocation of resources to reduce the renal failure with coexisting liver cirrhosis-related mortality burden.</p>