Celiac disease is a strongly heritable gastrointestinal illness that is an especially important model of the genetically complex multifactorial immune-mediated diseases¹. The HLA component of celiac disease (a specific HLA-DQ heterodimer)is largely established and is relatively uncomplicated^2,3, and the environmental component (gluten and related grain storage proteins in the diet) is remarkably well understood⁴. Previous family studies of celiac disease^5–8 suggested that there is at least one important non-HLA locus. This locus may be a stronger genetic factor than HLA⁷, and it apparently has a recessive mode of inheritance^5,6,8. We used a three-step genome screening protocol to identify loci that contribute to celiac disease in the western counties of Ireland, a region with the highest prevalence of celiac disease in the world⁹. The most significant of several possible non-HLA loci that we found was on chromosome 6p about 30 cM telomeric from HLA. It has a multipoint maximum lod score of 4.66 (compared with 4.44 for HLA-DQ) and appears to have a recessive mode of inheritance. Our study localizes and provides strong evidence for linkage of at least one non-HLA locus to celiac disease and may serve as a prototype for an efficient approach to screening the human genome for loci that contribute to complex diseases.