Analysis of 149 million deaths across 195 countries reveals sepsis accounts for 31.5% of all global deaths, claiming 21.4 million lives in 2021 alone. The condition, characterized by dysregulated immune responses to infection causing organ failure, affects 166 million people annually with case fatality rates varying dramatically by geography and underlying health systems. This represents the most comprehensive quantification of sepsis burden to date, drawing from multiple cause-of-death registries, hospital records, and tissue sampling across three decades. The findings underscore sepsis as arguably the leading killer worldwide, yet one that receives disproportionately little attention compared to its mortality impact. Unlike cancer or cardiovascular disease, sepsis cuts across all demographics and can complicate virtually any infection. The study's methodology—linking death certificates to hospital records and using advanced modeling to capture both explicit and implicit sepsis cases—likely provides the most accurate global picture yet achieved. For health systems, this data suggests sepsis prevention and early recognition should be universal priorities, not specialized concerns. The research also highlights stark global inequities, as sepsis disproportionately affects regions with limited healthcare infrastructure, making it both a medical and social justice imperative.