Hypothesis: Perioperative administration of a supplemented enteral formula may decrease postoperative morbidity. Design: Randomized clinical trial. Setting: Department of surgery at a university hospital. Patients: One hundred ninety-six registered malnourished patients (weight loss greater than or equal to 10%) who were candidates for major elective surgery for malignancy of the gastrointestinal tract. Intervention: After randomization (n= 150), one group received postoperative enteral feeding with a standard diet within 12 hours of surgery (control group; n = 50). Another group orally received 1 L/d for 7 consecutive days of a liquid diet enriched with arginine, omega-3 fatty acids, and RNA (preoperative group; n = 50). After surgery, patients were given the same standard enteral formula as the control group. A third group orally received 1 L/d for 7 consecutive days of the enriched liquid diet. After surgery, patients were given enteral feeding with the same enriched formula (perioperative group; n = 50). Main Outcome Measures: Postoperative complications and length of hospital stay. Results: The 3 groups were comparable for baseline demographics, biochemical markers, comorbidity factors, and surgical variables. The intent-to-treat analysis showed that the total number of patients with complications was 24 in the control group, 14 in the preoperative group, and 9 in the perioperative group (P=.02, control group vs perioperative group). Postoperative length of stay was significantly shorter in the preoperative (13.2 days) and perioperative (12.0 days) groups than in the control group (15.3 days) (P =.01 and P =.001, respectively, vs the control group). Conclusion: Perioperative immunonutrition seems to be the best approach to support malnourished patients with cancer.