Paneth cells, granulated epithelial cells located at the base of small bowel crypts, have a crucial role in innate immunity. Because controversies remain concerning Paneth cell numbers and function in celiac disease (CD), we quantified Paneth cells and human alpha-defensin (HD)-5 and HD-6 in 28 patients with uncomplicated CD, 8 patients with complicated CD (3 with ulcerative jejunoileitis, 2 with refractory sprue, and 3 with enteropathy-associated T-cell lymphoma), and 14 control subjects. Paneth cell numbers and proliferation did not differ in uncomplicated untreated and treated CD and control cases. However, the number of Paneth cells was significantly reduced in complicated CD. Mucosal HD-5 and HD-6 were comparable in uncomplicated untreated and treated CD and control cases. Ex vivo gliadin challenge of treated CD biopsy specimens had no effect on mucosal HD-5 and HD-6 transcripts. Paneth cell numbers and alpha-defensins are unchanged in the mucosa in uncomplicated CD. Further studies are needed to clarify the implications of reduction of numbers of Paneth cells in complicated CD.