Despite therapy advancements, amyloidosis mortality rates for older adults (aged ≥ 65) are rising. This study analyzes trends in amyloidosis-related mortality among older adults in the U.S. We conducted a cross-sectional analysis of death certificates from the CDC WONDER database for amyloidosis-related deaths from 1999 to 2020. Age-adjusted mortality rates (AAMRs) per 100,000 persons and annual percent change (APC) were calculated by age, race/ethnicity, urban-rural classification, and region. From 1999 to 2020, AAMR for amyloidosis in older adults (aged ≥ 65) in the U.S. increased from 2.7 to 5.6. Men consistently had higher AAMRs than women (men: 3.7 vs. women: 2.2 in 1999
men: 8.5 vs. women: 3.5 in 2020). In 2020, Non-Hispanic Blacks had the highest AAMR at 11.8, with an APC of 19.8 (95% CI 10.5-25.5). Regional differences were notable, with AAMRs highest in the Northeast (6.9) and lowest in the South (4.2). Large metropolitan areas had a higher AAMR (6.3) than non-metropolitan areas (4.6). Cardiac amyloidosis accounted for 68.8% of deaths, with AAMR rising from 1.7 to 4.2. There has been a significant increase in AAMRs for amyloidosis in the U.S. from 1999 to 2020, particularly among males, Non-Hispanic Blacks, and those in large metropolitan and Northeast areas. These findings stress the need for enhanced prevention and treatment strategies for older adults.