GOALS: To estimate the frequency and cause of nonresponsive celiac disease (CD). BACKGROUND: Treatment of CD is based on life-long adherence to a gluten-free diet (GFD). Some celiac patients experience persistence of symptoms despite a GFD. This condition is defined as nonresponsive CD. STUDY: Celiac patients on a GFD for at least 12 months underwent diet compliance assessment, laboratory tests, breath tests, endoscopic, and histologic evaluations according to the symptoms/signs reported. RESULTS: Seventy of 321 (21.8%) patients had persistent or recurrent symptoms/signs. The cause of symptom persistence was evaluated in 56 of 70 patients. Thirteen of 56 (23%) patients were antiendomysial antibody positive. Among the patients with negative serology, 1 had fibromyalgia, and 3 had evidence that disproved the diagnosis of CD. The remaining 39 patients with negative serology underwent duodenal biopsy sampling, which evidenced histologic alterations in 24 patients. Among the 15 patients with normal histology 3 were lactose intolerant, 9 had irritable bowel syndrome, 2 had gastroesophageal reflux disease, and in 1 patient a cause for the persistent symptom was not identified. In patients with confirmed diagnosis of CD, exposure to dietary gluten was the main cause of persistence of symptoms/signs, and consistently after dietary modification, symptoms resolved in 63% of the patients at later time points during follow-up. CONCLUSION: Nonresponsive CD occurs in nearly one fifth of celiac patients on GFD and its occurrence suggests further investigations to optimize the management of celiac patients.