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To identify the most efficient parenchyma transection technique for liver resection using a prospective randomized protocol.Liver resection can be performed by different transection devices with or without inflow occlusion (Pringle maneuver). Only limited data are currently available on the best transection technique.A randomized controlled trial was performed in noncirrhotic and noncholestatic patients undergoing liver resection comparing the clamp crushing technique with Pringle maneuver versus CUSA versus Hydrojet versus dissecting sealer without Pringle maneuver (25 patients each group). Primary endpoints were intraoperative blood loss, resection time, and postoperative liver injury. Secondary end points included the use of inflow occlusion, postoperative complications, and costs.The clamp crushing technique had the highest transection velocity (3.9 ± 0.3 cm2/min) and lowest blood loss (1.5 ± 0.3 mL/cm2) compared with CUSA (2.3 ± 0.2 cm2/min and 4 ± 0.7 mL/cm2), Hydrojet (2.4 ± 0.3 cm2/min and 3.5 ± 0.5 mL/cm2), and dissecting sealer (2.5 ± 0.3 cm2/min and 3.4 ± 0.4 mL/cm2) (velocity: P = 0.001; blood loss: P = 0.003). Clamp crushing technique was associated with the lowest need for postoperative blood transfusions. The degree of postoperative reperfusion injury and complications were not significantly different among the groups. The clamp crushing technique proved to be most cost-efficient device and had a cost-saving potential of 600 € to 2400 € per case.The clamp crushing technique was the most efficient device in terms of resection time, blood loss, and blood transfusion frequency compared with CUSA, Hydrojet, and dissecting sealer, and proved to be also the most cost-efficient device.