BACKGROUND: Laparoscopic cholecystectomy (LC) is being performed frequently in general surgery practice. Estimation of difficult cholecystectomy is very important to take precautions against complications. Cholecystokinin (CCK) is an important enzyme for gall bladder motility. CCK receptor is the target for CCK. Fibrosis and emptying problems of gallbladder are related with difficult cholecys tectomies. We aimed to evaluate the association between plasma CCK and difficult cholecystectomy and try to explain the mechanism. METHODS: Prospective cross-sectional study was conducted on a group of patients with cholelithiasis Patients who underwent elective cholecystectomy were classified into easy, difficult and very difficult preoperatively using LC difficulty scores. Pre-operative gallbladder empting ratios were measured by ultrasonography. Serum C-reactive protein, and postprandial serum CCK and pancreas polypeptide levels were measured before the operation. Operation data including operation times, adhesion scores, and complications were collected. Tissue CCK receptor levels and tissue fibrosis scores were obtained. RESULTS: Easy, difficult, and very difficult LC (DLC) groups were consisted of 34, 28, and 8 patients, respectively. Gallbladder emp tying was 60% in easy LC group, but 15% in very DLC group. Plasma CCK levels in easy group (37.4 pg/ml) were significantly lower than plasma CCK levels of difficult (58.6 pg/ml), and very difficult groups (66.23 pg/ml). Tissue CCK receptor levels of easy, difficult, and very difficult were 372.4, 178.3, and 144.1 ng/100 mg, respectively. Adhesion scores and fibrosis scores of very difficult group were significantly higher than other groups. Operation times were significantly longer in very difficult group. There were two conversions to open in very DLC group (25%). CONCLUSION: CCK is a reliable parameter for determining the difficulty of LC. Decreased CCK receptor levels with fibrosis of gallbladder are the probably responsible mechanism.