Class II histocompatibility antigens, known to be present on immunocompetent cells, were recently demonstrated on enterocytes. Because of their role in antigen presentation and immune response regulation, HLA-DR antigens were studied in patients with celiac disease. Cryostat sections of jejunal biopsy specimens were stained with several anti-DR monoclonal antibodies using an avidin-biotin peroxidase technique. Thirty patients with celiac disease either active (n = 5), in remission (n = 10), or in relapse (n = 15) were compared with 16 controls, 9 with a normal mucosa and 7 with a flat mucosa but without celiac disease. In celiac patients with active disease or in relapse, enterocytes were heavily stained on the surface epithelium and the crypts. This contrasted with the absence of crypt staining in the biopsy specimens of the other patients. Increase in DR expression was associated with an increase in the number of T8(+) lymphocytes in the crypts. Modulation of DR expression by enterocytes may be involved in the pathogenesis of celiac disease.