The aim of this randomized, double-blind clinical trial was to elucidate the impact of general anesthesia alone (GA) or supplemented with epidural anesthesia (EpiGA) on surgical stress response during laparoscopic cholecystectomy, using stress hormones, glucose, and C-reactive protein (CRP), as potential markers. Sixty-two patients scheduled to undergo elective laparoscopic cholecystectomy were randomly assigned into two groups to receive either GA or EpiGA. Stress hormones [cortisol (COR), human growth hormone (hGH), prolactine (PRL)], glucose, and CRP were determined 1 day before surgery, intraoperatively, and upon first postoperative day (POD1). Plasma COR, hGH, PRL, and glucose levels were maximized intraoperatively in GA and EpiGA groups and reverted almost to baseline on POD1. Significant between-group differences were detected for COR and glucose either intraoperatively or postoperatively, but this was not the case for hGH. PRL was elevated in GA group only intraoperatively. Although, CRP was minimally affected intraoperatively, a notable augmentation on POD1, comparable in both groups, was recorded. These results indicate that hormonal and metabolic stress response is slightly modulated by the use of epidural block supplemented by general anesthesia, in patients undergoing laparoscopic cholecystectomy cholecystectomy. Nevertheless, inflammatory reaction as assessed by CRP seems to be unaffected by the anesthesia regimen.