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BACKGROUND AND AIMS: Crohn's disease (CD) has emerged as a global disease, with the fastest rise in incidence in Asia. The impact of immigration (reflecting early-life exposure to one environment and later life to another) on disease phenotype, behavior, and seropositivity has not been examined previously.METHODS: We phenotyped a cohort of U.S.-residing (immigrant) South Asian patients with CD (SA-CD) and control subjects from 3 U.S. hospitals compared with native SA-CD and control subjects from India and Singapore. These cohorts were compared with a prospective cohort of 1679 U.S.-born White patients with CD (White-CD). Detailed disease phenotype, treatment, acculturation, environmental exposures, and serologies were ascertained.RESULTS: Our study consisted of 260 immigrant SA-CD and control subjects, 198 native SA-CD and control subjects, and 1679 White-CD. Both native (59%; P = .02) and immigrant (55%; P = .15) SA-CD demonstrated male predominance compared with White-CD (49%). The mean age at diagnosis for second-generation immigrants (17.7 years) was significantly lower than first-generation immigrants (34 years), native SA-CD (31.7 years) and White-CD (27.7 years); the age at diagnosis was also younger in Western/bicultural-identifying compared with Asian-identifying immigrants (P < .05). Second-generation patients with CD were more likely to have B1 disease compared with native and first-generation SA-CD (odds ratio, 3.48; P = .007). Immigrant patients with CD had higher frequency of perianal involvement compared with native SA-CD and White-CD. However, native-SA-CD more commonly had stricturing disease. The immigrant SA-CD cohort had higher CBir1 flagellin antibody (49%) and anti-outer membrane porin C antibody (19%) positivity rates than anti-Saccharomyces cerevisiae antibody (13%).CONCLUSIONS: Our international, multicenter study identified both commonalities as well as unique differences in disease phenotype, behavior, serological patterns, and environmental factors by geography and immigrant status. We highlight the importance of changing environment on CD phenotypic expression.