Endoscopic submucosal dissection (ESD) has been accepted as a minimal invasive alternative to surgery for localized superficial gastrointestinal neoplasms recently. However, the procedure remains to be technically challenging and time consuming. A new dissecting knife with partially insulated tip has been recently developed with built-in injection capability. The purpose of this study was to investigate whether the efficiency of ESD procedure could be improved with this new device. A total of 78 patients, who underwent ESD with gastric mucosal lesions including flat type polyps, adenoma or early gastric cancer, were randomly assigned to either ESD with O-type HybridKnife or conventional ESD knives without waterjet. Procedure time and related factors of ESD were analyzed. ESD procedure time was 43.0 (interquartile range, IQR 27.0-60.0) minutes in HybridKnife group compared to 60.5 (IQR 44.0-86.3) minutes in the control group (P = 0.001). There was no difference in the clinical outcome and the adverse event rate. The former demonstrated more favorable results in lesions ≤4 cm of specimen size (P ≤ 0.0001) and when located in the distal stomach (P = 0.001), also in lesions with fibrosis (P = 0.008). Multivariate regression analysis showed that O-type Knife (P ≤ 0.0001), specimen size (P ≤ 0.0001), and fibrosis (P ≤ 0.0001) were independent predictors of procedure time. The O-type HybridKnife yielded faster procedure time compared to the conventional knives in gastric ESD with a similar safety profile.