The aim of this study was to evaluate the potential advantages of perioperative versus postoperative administration of an enteral immune-enhancing diet on host defense and protein metabolism. Thirty subjects, candidates for gastrectomy for cancer, were randomly allocated into two groups. The first group (n = 15) received an enteral formula enriched with arginine, ω-3 fatty acids, and RNA 7 d before and 7 d after surgery; the second group (n = 15) received the same diet but only 7 d after surgery. Postoperative immune and inflammatory responses were investigated by phagocytosis ability of polymorphonuclear cells, interleukin-2 receptors (IL-2R), lymphocyte subsets, interleukin-6 (IL-6), and delayed hypersensitivity response (DHR). Prealbumin (PA), retinol binding protein, albumin, and transferrin were determined as protein synthesis indicators. Perioperative immunonutrition prevented the early postoperative impairment of phagocytosis, DHR, total number of lymphocytes, and CD4/CD8 ratio (P < 0.05 versus postoperative group). The IL-2R levels were significantly higher in the perioperative group (P < 0.05 versus postoperative on postoperative day [POD] 4 and 8). Perioperative group also showed lower levels of IL-6 (P < 0.05 versus postoperative on POD 1, 4, and 8) and higher levels of PA (P = 0.04 versus postoperative on POD 8). The perioperative administration of immunonutrition ameliorated the host defense mechanisms, controlled the inflammatory response, and improved the synthesis of short half-life constitutive proteins.