OBJECTIVES: Perianal disease (PD) is a frequent complication of Crohn's disease (CD). The lack of association between PD and development of intestinal penetrating disease may suggest that PD is a distinct phenotype with specific genetic or clinical risk factors. This study was undertaken to evaluate the role of genotype, clinical, and demographic characteristics with PD. METHODS: Phenotypic data on 121 CD patients with PD and 179 patients without PD were carefully characterized. The patients were genotyped for disease-associated OCTN1/2 and NOD2/CARD15 variants and the TNF-α promoter polymorphisms. Analysis was performed to evaluate the differences in phenotype and genotype frequencies between the PD group and the non-PD group. RESULTS: PD was associated with rectal involvement (odds ratio [OR] 2.27, 95% CI 1.32-3.91) and with Sephardic (non-Ashkenazi) Jewish ethnicity (OR 1.71, 95% CI 1.02-2.9). No association was found among the studied OCTN, NOD2, TNF-α variants and the risk for PD. CONCLUSIONS: The strongest factor associated with PD is rectal inflammation. OCTN1/2, NOD2/CARD15, and TNF-α promoter variants do not play a role in the risk to PD in the Jewish Israeli population. The association of ethnicity with PD may suggest that there are as yet unknown genetic variants that are associated with PD.