Mucosal addressin cell adhesion molecule 1, expressed on gut endothelial cells, in conjunction with integrin alpha(4)beta(7), expressed on lymphocytes, is critical in lymphocyte homing to the gut. The mucosal addressin cell adhesion molecule 1/integrin alpha(4)beta(7) pathway is involved in the pathogenesis of chronic intestinal inflammation by recruiting lymphocytes into inflamed gut. We explored the duodenal expression of mucosal addressin cell adhesion molecule 1 and the peripheral T-cell expression of integrin alpha(4)beta(7) in patients with celiac disease. Duodenal biopsies and a peripheral blood sample were collected from 15 celiac patients, before and after 12 months of gluten-free diet, and from 12 control subjects. Treated celiac biopsies were cultured with peptic-tryptic digest of gliadin and/or an anti-interferon alpha neutralizing antibody. Mucosal addressin cell adhesion molecule 1 was determined by confocal immunofluorescence microscopy and immunoblotting. Integrin beta(7)-positive T cells were analyzed by flow cytometry. Mucosal addressin cell adhesion molecule 1 expression was significantly higher in active celiac disease than in normal mucosa. After gluten-free diet, a dramatic reduction of mucosal addressin cell adhesion molecule 1 was also observed. No difference was seen between patients with celiac disease after treatment and controls. Ex vivo peptic-tryptic digest of gliadin challenge induced a marked increase of mucosal addressin cell adhesion molecule 1 expression. Blocking interferon alpha inhibited the peptic-tryptic digest of gliadin-induced mucosal addressin cell adhesion molecule 1 overexpression. The percentage of circulating beta(7)-positive T cells was significantly lower in untreated celiac disease in comparison to controls but normalized after gluten-free diet. Mucosal addressin cell adhesion molecule 1 is strongly up-regulated in active celiac disease dependent on interferon alpha and is associated with peripheral depletion of integrin alpha(4)beta(7)-expressing T cells. We conclude that mucosal addressin cell adhesion molecule 1 may represent an important determinant for the generation of mucosal damage in celiac disease.