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Sepsis and organ dysfunction are common and likely contribute to death after burn trauma. We sought to define relationships between sepsis, severe multiple organ dysfunction (MOD), and death after burn trauma.Adults with ≥ 20% total body surface area burns were prospectively enrolled. Information regarding infection, severity of sepsis, and organ failure was collected daily. Risk factors (e.g., age, burn size, shock) were analyzed for their association with severe MOD, complicated sepsis, and death. We characterized the temporal relationship between organ failure and sepsis.Of 175 patients, 27% developed severe MOD, 17% developed complicated sepsis, and 22% died. Full-thickness burn size, age, and inhalation injury were associated with MOD, sepsis, and death. Infection preceded MOD in 83% of patients with both. A base deficit of ≥ 6 mEq/L at 24 hours after injury was associated with death.When it occurs, severe MOD is usually preceded by infection. In addition, an elevated base deficit at 24 hours and septic shock are the most important factors associated with and possibly contributing to death after burn trauma.