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Routine serologic testing for celiac disease (CD) may be useful in irritable bowel syndrome (IBS) patients, but this is controversial. We aimed to compare the prevalence of unrecognized CD in a large cohort of patients with and without IBS.This is a family case–control IBS study conducted at a single US academic medical center. Stored serum and DNA were available. Tissue transglutaminase (TTg) immunoglobulin A was performed, followed by indirect immunofluorescence testing for endomysial antibodies with positive or weakly positive TTg results. Individuals were considered to have CD if both results were positive. χ2 and Fisher’s exact tests were used to compare prevalence between the two groups.Serum samples were studied from 533 cases and 531 controls. In all, 80% of participants were female, with a median age of 50 years; 65% of cases and 0% controls met the Rome criteria for IBS. Previous serological testing for CD had occurred in 142 (27%) cases and 13 (2%) controls, but none had CD on subsequent testing. Six (1.1%) cases versus five (0.9%) controls had positive or weakly positive TTg test. Six cases (1.1%) versus three (0.6%) controls were confirmed to have CD by endomysial antibody (P=0.51).No difference in the prevalence of CD between patients with IBS and patients without IBS at a tertiary medical center was observed. Our findings do not support routine celiac serologic or genetic testing in patients with IBS in all US populations.