Hypothesis: Reticuloendothelial system function is altered in patients with multiple trauma and organ failure: Design: Prospective cohort study. Setting: Surgical intensive care unit at a level I trauma center. Patients: Patients with multiple blunt trauma and injury severity scores greater than 20, with no referrals. Interventions: Every second day reticuloendothelial system (RES) clearance capacity and liver blood flow were determined by administering labeled human albumin. Liver function was measured by enzymatic decay of indocyanine green, and levels of plasma tumor necrosis factor α were evaluated. Results: In nonsurviving patients with blunt trauma, RES function was altered and was associated with organ dysfunction and infectious complications. Of 61 patients, 42 survived and 19 did not. Sixteen patients (84%) died of multiple organ failure. Significantly elevated RES activity (colloid clearance rate) was present between day 5 and day 13 after trauma in nonsurvivors (0.86 ± 0.16 [mean ± SD] on day 7, P = .003) compared with survivors (0.48 ± 0.08 on day 7) and 20 healthy volunteers (0.47 ± 0.06); RES activity then decreased to subnormal levels in nonsurvivors. Tumor necrosis factor α plasma levels were elevated early after injury only in nonsurvivors (on day 1: nonsurvivors, 1.2 ± 0.4 ng/mL [mean ± SD]; survivors, 0.5 ± 0.2 ng/mL; P = .02). Indocyanine green half-life values increased late after trauma, indicating late organ failure (on day 19: nonsurvivors, 111 ± 29 minutes [mean ± SD]; survivors, 12 ± 4 minutes; P≤.001). Conclusions: Early after trauma, nonsurviving patients demonstrated increased proinflammatory cytokine levels, followed by a state of pathological hyperactivation of the reticuloendothelial system prior to death. These results indicate that the stationary host defense system is involved in the mechanisms causing organ failure after severe trauma.