Seven hundred twenty-six patients from five pediatric intensive care units were studied to determine the association of multiple organ system failure (MOSF) with mortality and to test the hypothesis that MOSF associated with sepsis has a higher mortality rate than MOSF without sepsis. There were 177 (24%) patients with MOSF and 83 (11%) nonsurvivors of MOSF. The mortality rates for two, three, or four or more failed organ systems were 26%, 62%, and 88%, respectively (P less than 0.001). Eighty-four (47%) patients with MOSF had associated sepsis. Sepsis (both bacteremia and clinical sepsis syndrome) did not significantly increase mortality rates in the groups with organ system failure. Mortality rates for patients with sepsis before or within 24 hours of development of MOSF (early sepsis) did not differ from mortality rates for those patients with onset of sepsis more than 24 hours after developing MOSF (late sepsis, 53% vs 33%, P = NS). We conclude that underlying pathophysiologic mechanisms of MOSF other than sepsis are as important as sepsis in critically ill pediatric patients.