BACKGROUND The use of the Harmonic Scalpel (HS) for cystic duct ligation began with little data about its efficacy or safety. On the other hand, there is not any literature available about the use of PlasmaKinetic Sealer (PK) for closing the cystic duct in laparoscopic cholecystectomy (LC). Therefore, this study was designed to compare the efficacy and safety of HS and PK for achieving safe closure of the cystic ducts after LC. METHODS Ninety patients with symptomatic gallstone disease were enrolled in this prospective case control study. The patients were operated with laparoscopic technic and divided into three groups (n = 30) randomly. After the dissection of Calot's triangle, proximal cystic ducts on common bile ducts were sealed with single surgical clips (SC) in all groups, and in the first group, distal of the cystic ducts also was sealed with single SC and the gallbladders were removed with SC. In the second and third groups, distal of the cystic ducts were sealed with HS and PK, respectively. The gallbladders were removed as sealed cystic ducts with HS and PK. Then, gallbladders were connected to a transducer set and increasing pressure with saline was applied. The bursting pressures of gallbladders were measured and differences between the groups were calculated by using Student's t test. The value of P < 0.05 was accepted as significant. RESULTS In this study, the mean cystic duct bursting pressures were 332.46 ± 4.62 mmHg with SC, 326.56 ± 4.53 mmHg with PK, and 343.06 ± 4.28 mmHg with HS. Differences of the mean cystic duct bursting pressures between the groups were indicated the superior results of HS. CONCLUSIONS The results of this study indicated that HS is more effective than PK and as safe and effective as SC for cystic duct closure.