CD95 (APO-1/Fas), a cell surface receptor and member of the tumor necrosis factor receptor superfamily, induces apoptosis upon oligomerization. CD95 is broadly expressed in normal tissues. The CD95 ligand (CD95L) is a member of the tumor necrosis factor family of cytokines and exists in a membrane-bound and in a soluble form. In vitro, CD95L is expressed and released by activated T lymphocytes. The range of cell types capable of expressing CD95L in vivo is unknown so far. Using a specific probe for human CD95L and sensitive in situ hybridization, we examined CD95L mRNA expression along the gastrointestinal tract. The scarce lymphohistiocytic infiltrate within the lamina propria contained small subsets of medium-sized labeled cells, some of which bad short cytoplasmic protrusions and others of which were lymphoid in morphology. Autochthonous cells of the gastrointestinal tract did not contain any detectable transcripts except for Paneth cells that expressed CD95L mRNA at high levels. In ulcerative colitis, CD95L mRNA-positive inflammatory cells were increased in number, and metaplastic Paneth cells were the only epithelial cells expressing CD95L. Paneth cells are CD95 negative. Therefore, these cells may not commit CD95-mediated autocrine suicide. By secreting soluble CD95L, however, the Paneth cells might contribute to mucosal integrity.