This study was designed to evaluate the effects of a high‐protein formula enriched with arginine, fiber, and antioxidants compared with a standard high‐protein formula in early enteral nutrition in critically ill patients. For this study, 220 patients were enrolled in a prospective, multicenter, single‐blind, randomized trial in 15 Spanish intensive care units (ICUs). The primary endpoints were the incidence density rates of nosocomial infections, ICU and hospital length of stay, ICU and in‐hospital mortality, and mortality at 6‐month follow‐up. The patients in the control and study groups had similar baseline characteristics. The study group had a lower incidence of catheter‐related sepsis (0.4 episodes/1000 ICU days) than the control group (5.5 episodes/1000 ICU days), with a relative risk (RR) of 0.07 (95% confidence interval [CI] 0.01 to 0.54, p <.001). There were no differences in the incidence of ventilator‐associated pneumonia, surgical infection, bacteremia, or urinary tract infections between the 2 groups. ICU mortality (16% in the study group versus 21% in the control group; RR 1.5, CI 95% 0.7 to 2.9) and in‐hospital mortality (21% in the study group versus 30% in the control group; RR 1.6, CI 95% 0.9 to 3) were similar without differences in survival at 6‐month follow‐up (75% in the study group versus 68% in the control group, p =.15). Patients in the study group who were treated for 2 or more days showed a strong trend for better survival at 6‐month follow‐up (76% in the study group versus 67% in the control group, p =.06). Medical patients treated with the study diet had better survival than medical patients in the control group (76% in the study group versus 59% in the control group, p <.05). Critically ill patients fed a high‐protein diet enriched with arginine, fiber, and antioxidants had a significantly lower catheter‐related sepsis rate than patients fed a standard high‐protein diet. There were no differences in mortality or ICU and hospital length of stay. The subgroup of patients fed the study diet for >2 days showed a trend toward decreased mortality. (Journal of Parenteral and Enteral Nutrition 25:299–309, 2001)