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We retrospectively studied relations between age, pre-existing chronic disease, sepsis, organ system failure, and mortality in 487 patients from a medical ICU. Single organ system failure (SOSF) occurred in 136 (28%) and multiple (≥2) organ system failure (MOSF) in 187 (38%) patients. Cardiovascular and pulmonary failure predominated. Overall mortality was 27%. SOSF mortality was 16% and for MOSF 58%. Eighty-three percent of nonsurvivors had MOSF. Hence, MOSF is common and a major cause of death in critically ill medical patients. Advancing age and prior chronic disease may diminish physiologic reserve and predispose to sepsis and MOSF. Although sepsis is a major risk factor for MOSF, a nonspecific host response to critical illness may contribute to the syndrome in 35% of patients. Advancing age, chronic disease, and the number of failing organs, particularly failure of cardiovascular, pulmonary, renal, and neurologic systems, are major determinants of overall mortality, but sepsis is not an independent contributor.