In CD, associations with HLA have generally been weak or inconsistent. Recent observations in predominantly non-Jewish patients have suggested that HLA-DR3 may be “protective” in CD, i.e. decreased frequency among affected individuals. We have accumulated HLA-DR3 information on a large cohort of CD patients and analyzed the results by ethnic stratification. We find that the decreased frequency of the DR3 allele is more striking in the Ashkenazi Jewish population. Methods: As part of an ongoing study of genetic susceptibility, patients were recruited by doctor referral or patient self-referral in response to public advertising, as well as through direct solicitation via patient support organizations. Ethnic background was determined on all patients. HLA typing was performed on 80 CD patients and 84 healthy, ethnically matched Controls, by both serologic and oligonucleotide methods. Results: HLA-DR3 was relatively common in Controls, 31% (27/84), but occurred in only 12.5% (10/80) of the CDs, for a relative risk of 0.3 (moderately strong association). Among the Jewish subjects, all of whom were of Ashkenazi descent, the decrease in DR3 frequency was particularly striking, compared to ethnically matched Controls: ? Conclusion: While there was a trend for decreased DR3 in Non-Jews, Ashkenazi Jews have a strikingly diminished frequency of DR3, suggesting a “protective” effect.