Collagenous colitis is a rare cause of chronic watery diarrhea. In this condition, endoscopic findings are usually normal. Currently, the diagnosis relies on the histological presence of thick subepithelial bands of collagen deposits and an inflammatory infiltrate within the mucosa. However, these subepithelial bands may be developed only focally and may be too subtle to allow a definitive diagnosis upon routine hematoxylin and eosin (HE) and van Gieson's stainings. Recently, we and others were able to show a prominent staining of tenascin and type-VI collagen in the subepithelial band-like structures. In this study, we tested the diagnostic value of tenascin staining and type-VI collagen immunolocalization for the identification of collagenous colitis and compared it with conventional histology and histochemical detection of collagens. The analysis was based on 434 biopsy specimens of collagenous colitis, other forms of colitis, and normal mucosa. We were able to show that the immunohistochemical detection of increased amounts of tenascin, selectively in the subepithelial zone, is a specific test for collagenous colitis, with a sensitivity superior to conventional histological and histochemical detection, especially in minimal collagenous colitis (P<0.001). Of note, tenascin staining also allows the diagnosis of collagenous colitis in biopsies obtained only from the rectum and sigmoid colon, thus avoiding the need for colonoscopic investigations. Tenascin immunostaining is a simple and safe tool to complement conventional histological diagnostics in clinically and histopathologically unclear cases of diarrhea.