Background: Endoluminal gastroplication is used to treat GERD, with modest results. Little is known of the histologic reaction to endosutures. Thus, the histologic response to intraluminal plications at different penetration depths within the gastric wall was studied in an animal model. Methods: Intraluminal gastroplications were performed through a laparotomy in 18 New Zealand rabbits. Three sets of everted plications were placed at different penetration depths in each stomach: submucosa (SMpl), muscularis propria (Mpl), and serosa (Spl). Animals were randomized to survival times of 3, 10, or 60 days (respectively, Groups I, II, and III). Plications were compared with a grade scale for each histologic healing phase and gross inspection. Results: Fusion between folds was absent in all groups. Serosa differed from muscularis propria with respect to the proportion of samples with microscopic ischemia (67% vs. 8%; p = 0.015), remaining sutures in Group III (33% vs. 3%; p < 0.05 in a single test of significance, but correction for multiple testing removes this significance), and remaining plications in Group II (96% vs. 54%; p < 0.05 in a single test of significance, but correction for multiple testing removes this significance). All of the total and partial histologic scores for the corresponding healing phase in each group escalated with penetration depth. Overall comparison of the histologic scores showed a significant difference among the plications in the proliferation (Group II, p = 0.004) and maturation (Group II, p = 0.009) phases. Total scores also differed among the plications in Groups II (p < 0.001) and III (p < 0.001). Plications were absent in all of Group III, with Spl resulting only in a flat scar. Conclusion: Everted intraluminal gastroplications do not result in fusion between folds irrespective of suture-penetration depth. A flat scar is the final outcome and appears proportional to the amount of ischemia, foreign body reaction, and suture depth. (Gastrointest Endosc 2003;57:868-76.)