Administration of immuno-enhanced nutritional support may decrease postoperative morbidity, mortality, and infectious complications in cancer patients. The aim of this study was to verify that perioperative enteral diet, enriched with the nutrients arginine, ribonucleic acid (RNA), and ω-3 fatty acids improves outcomes of head and neck cancer patients undergoing major surgery. Forty patients with squamous cell carcinoma of the head and neck were studied. Group 1 received no preoperative nutritional support, whereas Group 2 received an oral formula with nutrients arginine, RNA, and ω-3 fatty acids. After surgery, Group 1 received a standard enteral formula, whereas Group 2 received an enriched enteral formula. Albumin (g/dl), prealbumin, fibrinogen, CRP, Il-6, and TNFa were measured 5 days before and 8 days after surgery. No statistically significant difference was observed for all the evaluated markers between postoperative and preoperative levels for both groups. The rate of complications was significantly reduced in the total number of patients receiving immunonutrition and in the particular subgroup of well-nourished patients receiving an immuno-enhanced diet. Perioperative enteral immuno-enhanced feeding in head and neck cancer patients undergoing major surgery may influence the postoperative outcomes by reducing the frequency rate of infections and wound complications.