This study has investigated the potential role of wheat in the pathogenesis of a naturally occurring enteropathy in Irish setter dogs. At eight months on a cereal-containing diet, jejunal biopsies from affected animals exhibited partial villus atrophy, increased intraepithelial lymphocytes, and distinct biochemical abnormalities in the brush border. Activities of alkaline phosphatase and leucyl-2-naphthylamidase were almost undetectable while disaccharidases were unaltered. Activity of 5'-nucleotidase (basolateral membrane) was low, and reduced malate dehydrogenase reflected a loss of mitochondrial activity, but other organelles were unaffected. Recovery was achieved on a wheat-free diet. Relapse on subsequent wheat challenge was characterized by partial villus atrophy and a selective effect on the brush border: modal density was decreased and there was a severe loss of brush-border alkaline phosphatase activity. These findings document a wheat-sensitive enteropathy in Irish setter dogs and suggest that brush-border alkaline phosphatase is specifically susceptible to damage by wheat.