Background and Objectives: This study examined whether perioperative multimodal analgesia (MMA) improves the effectiveness of intravenous nutrition (IVN) as a means of preventing protein wasting following major upper abdominal surgery (UAS). The MMA regimen utilized combined epidural opioid/local anesthetic and the systemic nonsteroidal anti-inflammatory drug (NSAID) ketorolac for 48 hours. Methods: In a prospective, randomized, nonblinded study, 47 patients scheduled for major UAS were allocated to receive the following: MMA [plusmn] intravenous lipid-based nutrition (IVN) or patient-controlled analgesia with opioids (PCA) [plusmn] IVN. Pain scores, nitrogen balance, total body protein (TBP), arterial blood gases, and various hormones were measured. Results: Pain control was significantly better in the MMA patients at rest and coughing. Only the MMA + IVN group maintained TBP, mean ([plusmn]95% confidence interval) preoperative day 1, 10.5 ([plusmn]1.0) kg; day 14, 10.7 ([plusmn]1.2) kg, whereas TBP decreased in the other groups (P = .04). Nitrogen balance was significantly greater in patients receiving IVN on day 7 (P = .01), but there was no effect related to the analgetic regimen. Decreased PaO2 seen on postoperative day 2 was not prevented by MMA. The hormonal response to surgery was not influenced by treatment modality, apart from a return to postprandial insulin levels on postoperative day 7 in those patients receiving IVN (P = .002). Conclusions: In conclusion, we have shown that the combination of MMA and IVN prevents protein loss and improves pain control after major UAS. Our results suggest that after UAS, MMA significantly reduced pain and, in combination with IVN, preserves total body protein and fat. This is the first direct evidence of such effects associated with a commonly used multimodal regimen. Reg Anesth Pain Med 2002;27:15-22.