Background and aim: A genetically impaired intestinal barrier Function has long been suspected to be a predisposing factor for Crohn’s disease (CD). Recently, mutations of the capsase recruitment domain family, member 15 (CARD15) gene have been identified and associated with CD. We hypothesise that a CARD15 mutation may be associated with an impaired intestinal barrier. Methods: We studied 128 patients with quiescent CD, 129 first degree relatives (CD-R), 66 non-related household members (CD-NR), and 96 healthy controls. The three most common CARD15 polymorphisms (R702W, G908R, and 3020insC)were analysed and intestinal permeability was determined by the lactulose/mannitol ratio. Results: Intestinal permeability was significantly increased in CD and CD-R groups compared with CD-NR and controls. Values above the normal range were seen in 44% of CD and 26% of CD-R but only in 6% of CD-NR, and in none of the controls. A household community with CD patients, representing a common environment, was not associated with increased intestinal permeability in family members. However, 40% of CD first degree relatives carrying a CARD15 3020insC mutation and 75% (3/4) of those CD-R with combined 3020insC and R702W mutations had increased intestinal permeability compared with only 15% ofwild-types, indicating a genetic influence on barrier function. R702W and G908R mutations were not associated with high permeability. Conclusions: In healthy first degree relatives, high mucosal permeability is associated with the presence of a CARD15 3020insC mutation. This indicates that genetic factors may be involved in impairment of intestinal barrier function in families with IBD. Background and aim: A genetically impaired intestinal barrier Function has long been suspected to be predisposing factor for Crohn’s disease (CD). Recently, mutations of the capsase recruitment domain family, member 15 (CARD15) gene have been identified and associated with CD. We hypothesized that a CARD15 mutation may be associated with an impaired intestinal barrier. Methods: We studied 128 patients with quiescent CD, 129 first degree relatives (CD-R), 66 non-related household members controls. The three most common CARD15 polymorphisms (R702W, G908R, and 3020insC) were analyzed and the intestinal permeability was determined by the lactulose / mannitol ratio. Results: Intestinal permeability was significantly increased in CD and CD-R groups compared with CD-NR and controls. Values ​​above the normal range were seen in 44% of CD and 26% of CD-R but only in 6% of CD-NR, and in none of the controls. A household community with CD patients, representing a common environmen However, 40% of CD first degree relatives carrying a CARD15 3020insC mutation and 75% (3/4) of those CD-Rs with combined 3020insC and R702W mutations had increased intestinal permeability Compared with only 15% of wild-types, indicating a genetic influence on barrier function. R702W and G908R mutations were not associated with high permeability. Conclusions: In healthy first degree relatives, high mucosal permeability is associated with the presence of a CARD15 3020insC mutation. This indicates that genetic factors may be involved in impairment of intestinal barrier function in families with IBD.