Endoscopic resection techniques, such as endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), are frequently aided by injection of submucosal lifting solutions that create a plane for dissection and protect deeper mural layers. ORISE™ gel is a recently approved synthetic lifting solution that produces a localized inflammatory reaction associated with retained gel at the injection site. We describe a series of six cases of ORISE™-associated inflammatory lesions in patients who underwent endoscopic resections. Deposits comprised pale fibrillary or hyalinized eosinophilic material, depending on their age. All cases were associated with an inflammatory reaction composed of foreign-body giant cells and scattered eosinophils. ORISE™ gel extended laterally and deeply beyond residual tumors in all cases. Histochemically, the material proved to be negative for Congo Red, and mucicarmine, faint blue with Alcian blue, but positive for PAS and PAS-D. It stained blue with trichrome. Such deposits were absent in cases, wherein other widely-available lifting solutions were used. We compared ORISE™ deposits to histologically similar extracellular deposits, namely amyloid and pulse granulomata. Unlike ORISE™ material, amyloid deposits appear as waxy, more densely eosinophilic material, and stain positive with Congo Red. Amyloid demonstrated prominent intramucosal and perivascular distributions, features not seen in this series of ORISE™ deposits. Hyalinized pulse granulomata showed strong overlap with ORISE™ deposits, since they also comprise eosinophilic material associated with giant cell reaction. On the other hand, they form ribbons of glassy material in circumscribed lobules, unlike the ill-defined ORISE™ deposits. In summary, we describe the pathologic findings at injection sites in patients who underwent endoscopic procedures aided by the recently approved lifting agent, ORISE™. Pathologists should be aware of its appearance and associated reaction to avoid confusion with other common extracellular deposits seen in the gastrointestinal tract.