Previous trials showed that perioperative immunonutrition improved outcome in patients with gastrointestinal cancer. This study was designed to appraise the impact of the simple preoperative oral arginine and n-3 fatty acids supplementation on immune response, gut oxygenation, and postoperative infections. Two hundred patients with colorectal neoplasm were randomized to: (a) oral intake for 5 days before surgery of a formula enriched with arginine and n-3 fatty acids (pre-op group; n = 50); (b) same preoperative treatment prolonged after surgery by jejunal infusion (peri-op group; n = 50); (c) oral intake for 5 days before surgery of a standard isoenergetic, isonitrogenous formula (control group; n = 50); and (d) no supplementation before and after operation (conventional group; n = 50). The immune response was measured by phagocytosis ability of polymorphonuclear cells and delayed hypersensitivity response to skin tests. Gut oxygenation and microperfusion were assessed by polarographic probes and laser Doppler flowmetry, respectively. The 4 groups were comparable for demographics, comorbidity, and surgical variables. The 2 groups receiving immunoutrients (pre-op and peri-op) had a significantly better immune response, gut oxygenation, and microperfusion than the other 2 groups. Intent-to-treat analysis showed an overall infection rate of 12% in pre-op, 10% in peri-op, 32% in control, and 30% in conventional groups (P <.04 pre-op and peri-op vs control and conventional). Preoperative oral arginine and n-fatty acids improves the immunometabolic response and decreases the infection rate. Postoperative prolongation with such supplemented formula has no additional benefit.