Background <p>Lung cancer and sepsis are major contributors to morbidity and mortality worldwide. Their coexistence represents a significant clinical challenge, as patients with lung cancer may be at increased risk of developing sepsis because of cancer-related immune dysfunction, treatment-related immunosuppression, and frequent healthcare exposure. Sepsis in these patients is associated with poor outcomes, increased health care utilization, and higher mortality rates.</p> Methods <p>We conducted a retrospective analysis of death certificates from the Centers for Disease Control and Prevention (CDC) WONDER database to evaluate mortality associated with the co-occurrence of lung cancer and sepsis among adults aged ≥ 45 years in the United States from 1999 to 2024. Age-adjusted mortality rates (AAMRs) and annual percent changes (APCs) were calculated and stratified by year, sex, race/ethnicity, census region, state, and metropolitan status.</p> Results <p>AAMR increased from 1.6 to 2.0 per 100,000 population between 1999 and 2024. Among males, the AAMR increased from 2.3 in 1999 to 2.4 in 2024, while among females, it rose from 1.1 to 1.6 over the same period. Racial disparities were evident, with non-Hispanic Black or African American adults experiencing the highest AAMR (2.6). Regionally, the South had the highest mortality burden (AAMR 2.2), while Kentucky and Mississippi reported the highest state-level rates (3.98 and 3.14, respectively). Mortality rates were higher in non-metropolitan areas (AAMR 1.9) compared with metropolitan areas (1.7).</p> Conclusions <p>Mortality associated with coexisting lung cancer and sepsis has increased over time, with notable disparities across demographic and geographic groups. These findings highlight the need for targeted public health strategies and improved access to care to reduce mortality in high-risk populations.</p> Graphical abstract <p></p>