The regenerating gene (REG) is a multigene family in humans that plays a role in tissue regeneration. The REG Iα protein is expressed in the pancreas and the gastrointestinal tract and is involved in the pathophysiology of gastritis, pancreatitis, cancer, inflammatory bowel disease, and type 1 diabetes (T1D). Celiac disease (CD) is an autoimmune disease caused by the ingestion of gluten in genetically susceptible individuals. Our aim was to determine whether the serum REG Iα concentration reflects the destructive/regenerative process in the small bowel in CD. REG Iα was determined by enzyme-linked immunosorbent assay (ELISA) in 40 patients with active CD, and in 19 of them, REG Iα was assessed after following a gluten free diet. As controls, 35 healthy subjects were included in the study. Autoantibodies to transglutaminase, gliadin, and endomisium were measured also. We found a significant increase in REG Iα in the sera of CD patients when compared with controls. REG Iα levels decreased after a gluten-free diet together with a significant reduction in antitransglutaminase antibodies. T1D and pernicious anemia patients displayed normal serum REG Iα concentrations. This preliminary study suggests that REG Iα protein levels can be used as a biomarker for the diagnosis and monitoring of CD. © 2011 Mosby, Inc. All rights reserved.