Exposure of esophageal epithelium to gastric and duodenal contents results in the histologic changes of hyperproliferation and mucosal thickening. We have previously shown that presence of secretory phospholipase A2 (sPLA2) is necessary to produce these histologic changes in a murine model of gastroduodenal reflux. We sought to determine the influence of gastroduodenal reflux (GDR) on sPLA2 protein and mRNA levels as well as enzyme activity in esophageal tissue. BALB/c (sPLA2+/+) mice (n = 28) underwent side-to-side surgical anastomosis of the first portion of the duodenum and GE junction (DGEA) resulting in continuous exposure of esophageal mucosa to mixed gastric and duodenal contents. Sham control mice (n = 14) underwent laparotomy, esophagotomy and closure. Real-time RT PCR was used to quantitate the influence of GDR on group IIa sPLA2 expression. Immunofluorescent staining was quantitated by digital microscopy using a specific antibody to identify and locate sPLA2 protein. A colorimetric assay was used to quantify total sPLA2 activity after standardization of protein levels. Statistical analysis was conducted using Student's t-test. Group IIa sPLA2 mRNA and protein levels were increased at 4 and 8 weeks compared with sham controls. This increase occurred in a time-dependent manner and correlated with esophageal mucosal thickness. Furthermore, sPLA2 enzyme activity was increased significantly at 4 and 8 weeks compared with untreated controls. The expression of group IIa sPLA2 as well as sPLA2 activity is induced by GDR. This novel finding indicates that sPLA2 may play a role in the development of the histologic changes produced by GDR in esophageal mucosa. © 2010 Copyright the Authors. Journal compilation © 2010, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.