Tumour necrosis factor (TNF)-alpha has been implicated in the pathogenesis of experimental and clinical enteropathy, but its exact role is unknown. We show here that a single dose of TNF-alpha causes significant small intestinal pathology in normal adult mice, which develops within 15 minutes, persists for up to 48 hours and is enhanced by interferon-gamma (IFN-gamma). The enteropathy consists of villus atrophy and crypt hyperplasia and is therefore similar to that found in immunologically mediated enteropathies such as graft-versus-host reaction (GvHR). TNF-alpha is also cytotoxic to an intestinal crypt cell line in vitro. Thus, a direct action of TNF-alpha on crypt cells may be involved in its enteropathic effects in vivo. Together, these findings indicate that TNF-alpha alone, or in concert with other cytokines, may be an important effector molecule in immunologically mediated intestinal pathology and may ultimately provide a target for specific immunotherapy for clinical enteropathies.