Objective:To determine whether early enteral feeding in a septic intensive care unit (ICU) population, using a formula supplemented with arginine, mRNA, and ω-3 fatty acids from fish oil (Impact), improves clinical outcomes, when compared with a common use, high protein enteral feed without these nutrients.Design:A prospective, randomized, multicentered trial.Setting:ICUs of six hospitals in Spain.Patients:One hundred eighty-one septic patients (122 males, 59 females) presenting for enteral nutrition in an ICU.Interventions:Septic ICU patients with Acute Physiology and Chronic Health Evaluation (APACHE) II scores of ≥10 received either an enteral feed enriched with arginine, mRNA, and ω-3 fatty acids from fish oil (Impact), or a common use, high protein control feed (Precitene Hiperproteico).Measurements and Main Results:One hundred seventy-six (89 Impact patients, 87 control subjects) were eligible for intention-to-treat analysis. The mortality rate was reduced for the treatment group compared with the control group (17 of 89 vs. 28 of 87;p< .05). Bacteremias were reduced in the treatment group (7 of 89 vs. 19 of 87;p= .01) as well as the number of patients with more than one nosocomial infection (5 of 89 vs. 17 of 87;p= .01). The benefit in mortality rate for the treatment group was more pronounced for patients with APACHE II scores between 10 and 15 (1 of 26 vs. 8 of 29;p= .02).Conclusions:Immune-enhancing enteral nutrition resulted in a significant reduction in the mortality rate and infection rate in septic patients admitted to the ICU. These reductions were greater for patients with less severe illness.