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Obstructive sleep apnea (OSA) and respiratory failure (RF) represent increasing clinical and public health challenges in the United States, yet national trends in mortality remain underexplored. This study evaluates trends in mortality associated with OSA and RF to highlight targeted prevention and management across demographics and regions. Using the CDC WONDER multiple cause of death (MCD) database, we retrieved death certificates from 1999 to 2023 to analyze mortality related to OSA and RF among adults aged ≥ 25 years. Age-adjusted mortality rates (AAMRs) per 100,000 were calculated and categorized by demographics and region. Joinpoint regression was used to estimate annual percent change (APC) and average APC. A total of 71,202 deaths occurred due to OSA and RF. The AAMR observed a significant and steep incline from 0.25 in 1999 to 2.26 in 2023 (AAPC: 9.3; 95% CI: 8.04 to 10.65, P < .01). Men had higher AAMRs than women (men: 0.32; women: 0.21) in 1999 to (men: 2.79; women: 1.85) in 2023. Racially, NH Blacks demonstrated the highest increase in AAMR from 0.53 in 1999 to 2.16 in 2023.The overall AAMR remained higher in nonmetropolitan areas compared to metropolitan areas (1.23 vs 1.01). Regionally, the Midwest recorded the greatest burden with AAMR increasing from 0.21 in 1999 to 2.55 in 2023. State-level AAMRs ranged from 0.58 (New York) to 1.92 (Nebraska) in 2020. Using nationwide retrospective data from 1999 to 2023, our study revealed that adults with concomitant OSA and RF face steadily rising mortality rates, with marked differences observed across demographic groups and geographic regions in the U.S., underscoring the importance of tailored strategies such as expanding access to early detection, and ensuring equitable healthcare delivery to reduce mortality and improve outcomes among such patients, particularly in disproportionately affected populations and regions.