The MIF gene has been associated with several diseases with inflammatory and autoimmune background, such as ulcerative colitis, rheumatoid arthritis and systemic lupus erythematosus. We aimed at testing the influence of two functional MIF promoter variants in celiac disease (CD) susceptibility. A (CAAT)(5-8) tetranucleotide repeat at position -794 and a single-nucleotide polymorphism at -173G/C were analyzed in the Spanish population (531 patients and 887 healthy controls). chi(2) statistics or Fisher exact test were used for comparisons. The -173C allele significantly increased risk ((CC+GC) vs GG: odds ratio (OR) (95% confidence interval (CI))=1.41 (1.10-1.81); P=0.005), as did carriage of the (CAAT)(7) allele (OR (95% CI)=1.36 (1.02-1.82); P=0.03) and of the haplotype (CAAT)(7)//-173C (OR (95% CI)=1.33 (1.00-1.76); P=0.04). Our data evidence for first time the role of the MIF gene increasing predisposition to CD. A common effect of MIF variants seems to underlie the etiology of these complex conditions.