Objective. To determine the effects of accidental injury of varying severity on interleukin (IL)-lα, IL-6, IL-8, tumor necrosis factor-α (TNF-α), and endotoxin release. Design. Prospective, multi-unit, longitudinal study. Setting. Emergency Departments and intensive care units of two university hospitals. Patients. Trauma patients after mild, moderate, and severe injury Interventions. None. Measurements and Main Results. Plasma cytokine and endotoxin concentrations were measured over a 5-day period, starting within 2 hrs of accidental injury. An enzyme-linked immunosorbent assay was used to determine plasma concentrations of IL-1α, IL-6, IL-8, and TNF-α. Plasma endotoxin concentrations were measured using a chromogenic limulus amebocyte assay. Preresuscitation samples obtained immediately on arrival in the Emergency Department, and within 2 hrs of injury, demonstrated significant increases of IL-6 and IL-8 concentrations in the severe injury group, in contrast to minimal increases seen after mild or moderate injury. Analysis of serial postresuscitation samples demonstrated rapid increases in IL-6 and IL-8 concentrations within 12 hrs of injury. IL-6 and IL-8 remained increased for 24 hrs after injury, then decreased markedly from their peak values during the next 24 hrs. Increased circulating concentrations of these cytokines continued to be present for >5 days in the severely injured patients. IL-6 and IL-8 concentrations were only minimally increased in patients 8 and 24 hrs after moderate injury. Endotoxin and IL-1α were not found in any samples, including those samples obtained serially from severely injured patients. No patient at any time point had TNF-α concentrations of >35 pg/mL. Conclusions. These results demonstrate that severe injury produces rapid, large increases in circulating concentrations of IL-6 and IL-8 that may contribute to the frequent development of the adult respiratory distress syndrome and multiple organ system failure in this clinical setting. (Crit Care Med 1993; 21:839–845)