Abstract The accelerated recovery of patients who undergo laparoscopic surgery is often attributed to the less traumatic approach. However, a growing body of evidence suggests that the capnoperitoneum specifically has antiinflammatory effects. While the cellular target of CO 2 has yet to be identified, the peritoneal macrophage is a prime target because of its major role in the inflammatory response. We hypothesized that the antiinflammatory effect of capnoperitoneum may be mediated via inhibition of peritoneal macrophage cytokine production. Male Sprague-Dawley rats were randomized to CO 2 pneumoperitoneum, anesthesia only, bacterial endotoxin (LPS) only, or saline ( n = 4 for all groups). Rats underwent 30 min of pneumoperitoneum or anesthesia followed immediately by intravenous injection of LPS. Controls received either LPS or saline without a prolonged exposure to anesthesia. One hour following LPS injection, peritoneal macrophages were harvested by peritoneal lavage and incubated for 3 h at 37°C in complete medium. IL-6 was measured during the ensuing 3 h using a standard ELISA kit. Values were normalized to cell number using the MTT uptake method. IL-6 production was significantly attenuated in macrophages derived from rats which had undergone capnoperitoneum and resembled the basal production found in macrophages harvested from saline controls ( P < 0.013 versus LPS and P < 0.03 versus Isoflurane). Macrophages harvested from rats having undergone anesthesia alone produced IL-6 in similar quantities to macrophages from LPS-treated controls. All samples were measured in duplicate and normalized to viable cell number. These results confirm our hypothesis and demonstrate that the advantages of laparoscopic surgery are in part mediated by the peritoneal macrophage. Capnoperitoneum when applied prior to an inflammatory insult in vivo significantly attenuates cytokine production.