Background and Aims: Integrins play diverse roles in cellular actions and signaling in the immune system. In the context of mucosal immune responses, the integrin α4β7 has received particular attention because of its intimate involvement in lymphocyte recruitment to normal gastrointestinal mucosa and associated lymphoid tissue. The aim of this study was to determine the functional relevance of α4β7 in the pathogenesis of colonic inflammatory disease using the colitic cotton-top tamarin, an animal model of human ulcerative colitis. Methods: Chronically colitic cotton-top tamarins were given either a cross-reactive monoclonal antibody to human α4β7 or an irrelevant control monoclonal antibody. The animals were then evaluated clinically and mucosal biopsy specimens assessed by histological and quantitative morphometric analysis. Results: A blocking monoclonal antibody to α4β7 integrin ameliorated inflammatory activity and rapidly improved stool consistency when administered to chronically colitic animals. Furthermore, using morphometric analysis of biopsy specimens, antibody therapy reduced the mucosal density of α4β7+ lymphocytes and α4β7- neutrophils and macrophages. Conclusions: These results suggest that the α4β7 integrin represents a novel, potentially organ-specific therapeutic target for the treatment of inflammatory bowel disease.