Background and Aim: When carrying out endoscopic submucosal dissection (ESD), procedural safety increases with greater tissue elevation and efficiency increases with longer-lasting submucosal cushion. Fluids specifically developed for ESD in Asia are not commercially available in the West, leaving endoscopists to use a variety of injectable fluids off-label. To determine the optimal fluid available in the West, we compared commonly used fluids for Western ESD. Methods: All phases were carried out in an ex vivo porcine stomach model. Phase 1 compared tissue elevation and duration of submucosal cushions produced by various standard volumes of various injectable solutions used for ESD. The two best-performing solutions used off-label were tested head-to-head in ESD in Phase 2. Phase 3 compared the best solution from Phase 2 to Eleview®, currently the only submucosal injection fluid approved in the USA. In Phases 2 and 3, five ESD were carried out with each solution. The solutions were randomized and the endoscopist blinded to the solution. Results: The best-performing solutions in Phase 1 were 0.4% hyaluronic acid, 6% hydroxyethyl starch (HES), and Eleview®. Phase 2 compared 6% HES and hydroxypropyl methylcellulose (HPMC), showing that ESD with 6% HES was easier (P = 0.007), faster (P = 0.041) and required less injection volume (P = 0.003). In Phase 3, resection speed, ease of ESD and total volume per area resected were comparable between 6% HES and Eleview®. Conclusions: Of the submucosal injection fluids currently available in the West, Eleview® and 6% HES are the best-performing solutions for ESD in a porcine model.