e23258 Background: Esophageal cancer (EC) is the sixth leading cause of cancer-related deaths in the United States, with a mere 20% survival rate in the first five years, making it a significant public health concern. Considering the lack of comprehensive evaluations of mortality trends that are undergoing substantial transformations on a global scale, this study aims to provide an update on the mortality rates of esophageal cancer and its trends in the United States. Methods: The mortality trends among adults with EC were analyzed using data from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiological Research (CDC WONDER) database, where EC was presented as a contributing or the underlying cause of death. Code C15 “Malignant Neoplasms of Esophagus” in the International Classification of Disease, tenth revision (ICD-10) was used to identify the data. Crude and age-adjusted mortality rates (AAMRs) per 100,000 people were extracted. Annual percent changes (APCs) in AAMRs with 95% CI were obtained using joint point regression analysis across different demographic (sex, race/ethnicity, and age) and geographic (state, urban-rural, and regional) subgroups. Results: Between 1999 and 2020, 309,725 documented deaths were attributed to esophageal cancer. The overall AAMR decreased from 1999-2020 (6.69 to 5.68). Males had higher consistently higher AAMRs than females (10.96 vs. 2.24). NH White had the highest overall AAMR (6.88), followed by NH Black (6.46), NH American Indian (4.95), Hispanic or Latino (3.31), and NH Asian or Pacific Islander (2.57). CMRs also increased with advancing age and were greatest in individuals over the age of 85 years. AAMR also varied by region (overall AAMR: Midwest: 7.18; Northeast: 6.75; South: 6.07; West: 5.76), and non-metropolitan areas had higher AAMR (non-core areas: 7.09; micropolitan areas: 7.19) than metropolitan areas (large central metropolitan areas: 5.75; large fringe areas: 6.33). The states in the upper 90th percentile of esophageal cancer-related AAMR were Vermont, District of Columbia, West Virginia, Ohio, New Hampshire, and Maine, and exhibited an approximately two-fold increase in AAMRs, compared to states falling in the lower 10th percentile. Conclusions: Over the last two decades, there has been an overall decline in mortality related to EC in the United States. However, demographic and geographic discrepancies in EC-related mortality persist, necessitating additional exploration and development of specifically directed treatments.