This study investigated the influence of an enteral diet supplemented with arginine, omega-3 fatty acids, and nucleotides (Impact, Sandoz Nutrition, Berne, Switzerland) on the incidence of systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF) in patients after severe trauma. Thirty-two patients with an injury-severity score > 20 were included in this prospective, randomized, double-blind, controlled study. Primary endpoints were the incidence of SIRS and MOF. Secondary endpoints were parameters of acute phase and immune response as well as infection rate, mortality, and hospital stay. For statistical analysis 29 patients (test group n = 16, control n = 13) were eligible. In the test group, significantly fewer SIRS days per patient were found during 28 d. The difference was highly significant between d 8-14 (P < 0.001). MOF score was significantly lower in the test group on d 3 and d 8-11 (P < 0.05). Acute phase parameters showed lower C-reactive protein serum levels (significant on D day 4) and fibrinogen plasma levels (significant on d 12 and 14; P < 0.05). HLA-DR expression on monocytes showed significantly higher fluorescence activity on d 7. No significant difference was found for T-lymphocyte CD4/CD8 ratio, interleukin-2 receptor expression, infection rate, mortality (2/16 vs. 4/13), and hospital stay. The results of the study provide further support for beneficial effects of arginine, omega-3-fatty acids and nucleotide-supplemented enteral diet in critically ill patients.