Abstract Background and study aims Endoscopic resection requires use of submucosal injection. This study was conducted to assess efficacy and impact on early healing of hyaluronic acid combined with chondroitin sulfate and poloxamer 407 (Ziverel) when used as a solution for submucosal injection. Materials and methods Prospective and comparative study of gastric endoscopic mucosal resection (EMR) with three groups of two Yorkshire pigs. Six submucosal cushions were created in each animal by injecting 2 mL of Ziverel (Group 1) or succinylated gelatin (SG) (Group 2), enabling 12 EMR in each group. Submucosal cushions were created with Ziverel in Group 3, without resection. Electrosurgery unit settings were the same in all cases. EMR defects and injection sites were marked with clips. The animals were sacrificed 7 days later. EMR specimen size and duration of procedure were recorded. EMR specimens and EMR scars and injection sites were evaluated by a blinded pathologist. Results We successfully performed 24 EMR (15 en-bloc and 9 piecemeal, without differences between groups 1 and 2). Mean EMR specimen dimensions were significantly larger in Group 1 (median 19 mm, range 6 – 40 vs 16.6 mm, range 5‑25; P = 0.019), without changing the electrocautery unit settings. Blinded histopathologist assessment of EMR specimens showed less fibrosis in the submucosa and a trend to fewer cautery artifacts with Ziverel and did not identify any significant differences in early healing of resection sites. Conclusion The combination of Ziverel enables EMR and does not negatively affect early healing.