Gastrointestinal endocrine tumors (GETs) are neoplasms of uncertain etiopathogenesis that often show a prominent fibroblast and smooth muscle cell proliferation within the tumor stroma. Acidic fibroblast growth factor (aFGF) and transforming growth factor-alpha (TGF alpha) are potent mitogens for both mesenchymal and epithelial cells, and their biologic activities depend on binding to specific receptors, including fibroblast growth factor receptor-4 (FGFR4) and epidermal growth factor receptor (EGFR). To evaluate the roles of these growth factors and their respective receptors in the pathogenesis of stromal lesions and tumor growth, we investigated their immunohistochemical expression in 43 normal gastrointestinal mucosa samples and 53 GETs. aFGF expression was found in a subgroup of enterochromaffin (EC) cells of the gastric and intestinal mucosa, whereas FGFR4 was localized only in colorectal L cells. TGF alpha was expressed in intestinal EC cells and colorectal L cells, whereas EGFR was not detected in any gut endocrine cell. aFGF was localized in all EC-cell neoplasms and was coexpressed with FGFR4 in most cases. This receptor was also found in all L-cell tumors and in a few of the other types of GETs. EGFR was not detected in any of the GETs examined. Several stromal cells of GETs, including fibroblasts and smooth muscle cells, showed FGFR4 and EGFR immunoreactivity. Tumors expressing both aFGF and TGF alpha presented a stroma that was more abundant than that of GETs expressing none or only one of these factors. These results suggest that FGFR4 expression may be involved in the development of EC-cell tumors through an autocrine mechanism, and that the abundant fibromuscular stroma may be related to the concurrent production of both aFGF and TGF alpha by tumor cells.