Prion diseases or transmissible spongiform encephalopathies have been shown to be communicated by oral ingestion of the infectious agent. However, the exact route of transmission is still unknown. In order to better understand the pathophysiology of these diseases, it is crucial to identify cell types of peripheral tissues in which the infectious agent may propagate. Since expression of cellular prion protein (PrPc) is a prerequisite for prion replication, we determined the expression of PrPc in the mucosa of the gastrointestinal tract using immunohistochemistry. Expression of PrPc was negative or weak in the neck region of the gastric mucosa and moderate to strong in crypts of both the small and the large bowel. PrPc was found to be upregulated in the mucosa of patients with Helicobacter pylori gastritis. In contrast, PrPc staining appeared to be downregulated in patients with inflammatory disorders of the large bowel and it remained moderate to strong in inflammatory disorders of the small bowel. Our results support the notion that epithelial cells of the gastrointestinal tract may represent a possible target for prion entry and replication.