Background: The initial response of esophageal mucosa to gastroduodenal reflux is inflammation and hyperplasia. Secretory phospholipase A2 (sPLA2) is a known mediator of gut inflammation, and its levels are increased in Barrett's esophagus. We hypothesized that the sPLA2 gene is required to produce esophageal mucosal hyperplasia in response to gastroduodenal reflux. Methods: C57BL/6 (n = 5) sPLA2-/- mice and C57BL/6Cg-Tg(PLA2G2A)703N16 mice (n = 4) sPLA2-/+ underwent a side-to-side surgical anastomosis between the duodenum and gastroesophageal junction (DGEA). Control animals [sPLA2-/- (n = 5), sPLA2-/+ (n = 4)] underwent laparotomy with incision and repair of the esophagus. Tissue was harvested after 4 weeks, and H&E staining was performed to quantify esophageal mucosal thickness. Ki67 and sPLA2 immunostaining were performed to quantitate differences in cell division and sPLA2 expression. Results: Mice expressing human sPLA2 had a 2. 5-fold increase in thickness of the esophageal mucosa as compared to controls (p = 0. 01). A 6. 5-fold increase in proliferation (p = 0. 02) and a twofold increase in sPLA2 expression (p = 0. 04) were demonstrated in animals exposed to gastroduodenal reflux. Conclusions: The presence of sPLA2 is necessary for early mucosal hyperplasia produced by exposure of the esophagus to gastroduodenal contents. sPLA2 expression is upregulated by gastroduodenal reflux, strengthening its role as a critical mediator of early mucosal hyperplasia. © 2009 The Society for Surgery of the Alimentary Tract.