BACKGROUND: African Americans (AAs) are an admixed population of West African (WA) and European ancestry (EA). Crohn’s disease (CD) susceptibility genes have not been established. We therefore evaluated the contribution of European admixture and major established risk genes to AA CD. METHODS: Ninety-seven admixture informative markers were genotyped for ancestry estimates using STRUCTURE. Overall, 354 AA CD cases and 354 ethnicity-matched controls were genotyped for total 21 single nucleotide polymorphisms (SNPs) in ATG16L1, NOD2, IBD5, IL23R and IRGM by TaqMan or direct sequencing. Association was evaluated by logistic regression, adjusted for ancestry. RESULTS: Mean EA was similar among the CD cases and controls (20.9% and 20.4%, respectively, P = 0.58). No significant admixture differences were observed among 211 to 227 cases stratified by phenotypic subclassifications including onset, surgery, site, and behavior. CD was associated with NOD2 carrier (6.93% CD, 2.15% Controls, P = 0.007), ATG16L1 Thr300Ala (36.1% CD, 29.3% Controls, P = 0.003), SLC22A4 and SLC22A5 (IBD5 locus) functional SNPs (Leu503Phe [10.5% CD, 7.6% Controls, P = 0.05] and g-207c [41.3% CD, 35.7% Controls, P = 0.03], respectively), and IL23R rs2201841 (18.2% CD, 13.8% Controls, P = 0.03), but not IRGM variants, nor three African ancestral NOD2 nonsynonymous variants. IBD5 risk was recessive. An all-minor allele IBD5 haplotype from EA was associated (P = 0.05), whereas a more common haplotype isolating g-207c was not. CONCLUSIONS: Specific functional gene variations contribute significantly to AA CD risk. Established NOD2, SLC22A4-A5, and ATG16L1 variants show increased CD risk, with IBD5 recessive. Although CD is more common in whites, European admixture is similar among AA cases and controls.