BACKGROUND: Laparotomy under general anesthesia is associated with depressed natural killer cell cytotoxicity (NKCC) and compromised clearance of tumor cells. We tested the hypothesis that awake epidural anesthesia (AEA) improves NKCC compared to conventional general endotracheal anesthesia (GEA). PATIENTS AND METHODS: Preoperative, perioperative, and postoperative (day 3) NKCC, plasma epinephrine, norepinephrine, cortisol levels, and 24-hour urinary cortisol levels were measured in 20 patients undergoing open colectomy under either AEA or GEA. RESULTS: Preoperative and postoperative measurements were not significantly different in the two groups. Patients receiving GEA had a significant reduction in NKCC from 36% ± 4% preoperatively to 22% ± 4% perioperatively (P = 0.02). Patients receiving AEA had no significant change in NKCC. Perioperative plasma epinephrine and cortisol levels were higher with GEA than AEA. The perioperative 24-hour urinary cortisol excretion values were significantly higher in the group receiving GEA, suggesting a greater stress hormone response in this group compared to AEA patients. CONCLUSIONS: Compared to GEA, AEA appears to preserve perioperative NKCC. This effect may be related to an attenuated stress hormone response associated with AEA. Cancer patients may have improved killing of embolized tumor cells during surgery performed under AEA.