Background: Formation of a submucosal fluid cushion has become integral to endoscopic mucosal and polyp resection. Solutions available for injection into the submucosa of the GI tract create short-lasting submucosal fluid cushions or are costly. The feasibility, durability, and histologic response to submucosal fluid cushions created by injection of hydroxypropyl methylcellulose were studied in the esophagus of pigs. Methods: Thirty-six esophageal submucosal fluid cushions created with hydroxypropyl methylcellulose were studied in 12 animals divided in 2 groups of 6 animals each. In Group I, 18 submucosal fluid cushions were created by submucosal injection of hydroxypropyl methylcellulose followed by tattooing. In Group II, 18 submucosal fluid cushions were created by submucosal injection of hydroxypropyl methylcellulose, with sites marked by an endoscopically placed suture. In all cases, the duration of the submucosal fluid cushion was measured. After 7 days, submucosal fluid cushion sites were assessed by EGD, necropsy, and histologic evaluation. Results: The mean submucosal fluid cushion duration was 36 minutes (3-45 minutes) and 38 minutes (5-45 minutes) for, respectively, Groups I and II. EGD and necropsy after 1 week showed normal-appearing mucosa at the site of all submucosal fluid cushions in both groups. Some Group I animals additionally had nodules at the tattoo sites. Histologic assessment demonstrated minimal alterations in 33 of 36 (92%) submucosal fluid cushion sites and localized mild inflammatory reaction in 3 of 36 (8%). In Group I, 8 of 18 (44%) tattoo sites exhibited a significant inflammatory reaction, including 3 abscesses. Conclusions: Hydroxypropyl methylcellulose creates a long-lasting submucosal fluid cushion with minimal tissue reaction and should be considered a low-cost option for creating submucosal fluid cushions. The use of tattooing with carbon black should be carefully considered when histologic study is required to assess potential inflammatory tissue responses to an invasive technique or instillation of foreign material in the GI tract. (Gastrointest Endosc 2003;57:41-7.)