In general, laparoscopic cholecystectomy produces a surgical stress response very similar to which occurs after open cholecystectomy. The question is whether the pneumoperitoneum constitutes a significant pathophysiologic trauma, which might be followed by profound changes in the stress response. We conducted a prospective, randomized trial involving 50 consecutive patients scheduled for laparoscopic cholecystectomy, who had a body mass index equal to or less than 30 kg/m(2) with no acute cholecystitis, pancreatitis, or liver or renal disease. These patients were randomized to undergo either the gasless (GLC, n = 24) or the carbon dioxide pneumoperitoneum (CLC, n = 26) procedure. Perioperative assessment of cortisol, insulin, glucose, and C-reactive protein levels was the main determinant of outcome. During the operative procedure, significantly higher levels of serum cortisol and insulin were found in the CLC group than in the GLC group (P < 0.05). No difference in glucose levels was observed between the two groups. The inflammatory response was moderate in both groups. However, on postoperative day 1 the median C-reactive protein level was significantly higher in the GLC group than that in the CLC group (P < 0.05). Carbon dioxide and the positive intra-abdominal pressure during conventional laparoscopy may contribute to the activation of the surgical stress response.