BACKGROUND: This study evaluates the effectiveness of PuraLift, a novel self-assembling peptide-based submucosal injection solution, in endoscopic submucosal dissection (ESD) procedures. We compared its performance to MucoUp in a variety of organ-spanning lesions (esophagus, stomach, and colon/rectum). METHODS: We included 40 consecutive ESD lesions from our hospital, with 19 treated using PuraLift and 21 using MucoUp. Special cases (such as those with ulcerative colitis, evident fibrosis due to post-treatment scars, and circumferential esophageal cases) and the cases that used device without waterjet function were excluded. Endoscopists assessed the satisfaction of submucosal lifting through needle injection on a 5-point scale. Firmness during local injection by the assistant for the PuraLift group was compared to MucoUp (MucoUp was set as a baseline score of 3) using a 5-point scale. RESULTS: The firmness during local injection was significantly lower with PuraLift compared to MucoUp across all locations: esophagus (1 (1-2) vs. 3 (3-3), p = 0.018), stomach (1.5 (1-2) vs. 3 (3-3), p <
0.001), and colon/rectum (2 (1-2) vs. 3 (3-3), p <
0.001). However, there were no significant differences between PuraLift and MucoUp in terms of endoscopist satisfaction with lifting, amount of solution injected, glycerol used via jet function, or procedure time for any organ. CONCLUSION: PuraLift, with its novel mechanism, offers comparable lifting satisfaction to MucoUp but with less firmness during injection. It presents a promising alternative as a local injection solution in ESD procedures.