The study analyzed trends in respiratory failure mortality in US adults aged 45 and older from 1999 to 2023 using the CDC WONDER database. A total of 186,075 deaths related to respiratory failure (ICD-10 code J96) were recorded. The age-adjusted mortality rate (AAMR) increased from 3.71 per 100,000 population in 1999 to 10.50 in 2023, with the largest increase between 2005 and 2018 (APC +7.96%). In 2023, mortality was higher for men (AAMR 11.14) than women (9.94), non-Hispanic blacks (14.07) versus Hispanics (5.96), and rural (12.27) versus large metropolitan areas (8.86). Differences were also observed according to census regions. A sensitivity analysis with lung cancer as the underlying cause and respiratory failure as a contributor confirmed these trends.