Excessive proinflammatory activation after trauma plays a role in late morbidity and mortality, including the development of multiple organ dysfunction syndrome (MODS). To date, identification of patients at risk has been challenging. Results from animal and human studies suggest that circulating interleukin 6 (IL-6) may serve as a biomarker for excessive inflammation. The purpose of this analysis was to determine the association of IL-6 with outcome in a multicenter developmental cohort and in a single-center validation cohort. Severely injured patients with shock caused by hemorrhage were evaluated within a multicenter developmental cohort (n = 79). All had blood drawn within 12 h of injury. Plasma IL-6 was determined by multiplex proteomic analysis. Clinical and outcome data were prospectively obtained. Within this developmental cohort, a plasma IL-6 level was determined for the subsequent development of MODS by developing a receiver operating curve and defining the optimal IL-6 level using the Youden Index. This IL-6 level was then evaluated within a separate validation cohort (n = 56). A receiver operating curve was generated for IL-6 and MODS development, with an IL-6 level of 350 pg/mL having the highest sensitivity and specificity within the developmental cohort. IL-6 was associated with MODS after adjusting for Acute Physiology and Chronic Health Evaluation, Injury Severity Score, male sex, and blood transfusions with an odds ratio of 3.9 (95% confidence interval, 1.33 - 11.19). An IL-6 level greater than 350 pg/mL within the validation cohort was associated with an increase in MODS score, MODS development, ventilator days, intensive care unit length of stay, and hospital length of stay. However, this IL-6 level was not associated with either the development of nosocomial infection or mortality. Elevation in plasma IL-6 seems to correlate with a poor prognosis. This measurement may be useful as a biomarker for prognosis and serve to identify patients at higher risk of adverse outcome that would benefit from novel therapeutic interventions.