Background: Equine inflammatory small bowel disease (ISBD) is an idiopathic pathologic condition seeming to increase in prevalence. Objective: To investigate the potential role of gluten in equine ISBD. Animals & Methods: Antibodies known to be important in the diagnosis of human coeliac disease (CD): IgA antibodies to human recombinant and guinea pig tissue-transglutaminase (TGA), native gliadin (AGA), deamidated-gliadin-peptides (DGPA), and primate and equine endomysium (EMA) were assessed in blood samples from three different groups of horses: ISBD affected (n ¼ 12) on a gluten-rich diet and controls either on gluten-rich (n ¼ 22) or gluten-poor (n ¼ 25) diets. Significant differences ( p < 0.05) between groups were assessed using the Wilcoxon test. Results: Both ISBD-affected horses and gluten-rich controls had significantly ( p < 0.0004) higher hrTGA titers than gluten-poor controls. However, ISBD horses did not show significantly increased levels of any of the CD related antibodies when compared to gluten-rich controls. Nevertheless, markedly increased antibody levels (TGA, EMA and DGPA) were found in one of the ISBD horses. The introduction of a gluten-free ration in this 14-year-old warmblood stallion resulted after 6 months in the reduction of antibody levels and clinical recovery associated with improved duodenal histopathology. Conclusion: To the best of our knowledge, this is the first study assessing gluten-related antibodies in horses and results suggest a potential pathogenic role of gluten in at least some cases of equine ISBD. Clinical importance and impact for human medicine: Given serology and concurrent clinical findings, this study warrants further investigations into the immunologic basis of possible gluten-sensitive enteropathy in horses and analogy with human disease.