Interactions between the epithelium and surrounding mesenchyme/stroma play an important role in normal gut morphogenesis, the epithelial response to injury, and epithelial carcinogenesis. The tumor microenvironment, composed of stromal cells including myofibroblasts and immune cells, regulates tumor growth and the cancer stem cell niche. Deletion of epimorphin (Epim), a syntaxin family member expressed in myofibroblasts and macrophages, results in partial protection from colitis and from inflammation-induced colon cancer in mice. We sought to determine whether epimorphin deletion protects from polyposis in the Apc^min/+ mouse model of intestinal carcinogenesis. Methods: Epim^-/- mice were crossed to Apc^min/+ mice; Apc^min/+ and Apc^min/+ /Epim^-/- mice were sacrificed at 3 months of age. Polyp numbers and sizes were quantified in small intestine and colon, and gene expression analyses for pathways relevant to epithelial carcinogenesis were performed. Primary myofibroblast cultures were isolated, and expression and secretion of selected growth factors from Apc^min/+ and Apc^min/+ /Epim^-/- myofibroblasts was examined by ELISA. Results: Small bowel polyposis was significantly inhibited in Apc^min/+ /Epim^-/- compared to Apc^min/+ mice. Apc^min/+ /Epim^-/- compared to Apc^min/+ polyps and adjacent uninvolved intestinal mucosa had increased TGFβ expression and signaling with increased P-Smad2/3 expression. Myofibroblasts isolated from Apc^min/+ /Epim^-/- vs. Apc^min/+ mice had markedly decreased hepatocyte growth factor (HGF) expression and secretion. Conclusions: Epim deletion inhibits polyposis in Apcmin/+ mice, associated with increased mucosal TGFβ signaling and decreased myofibroblast HGF expression and secretion. Our data suggest that Epim deletion reduces tumorigenicity of the stromal microenvironment.