Matrix metalloproteinases (MMPs), such as stromelysin-1 (MMP-3), are a family of enzymes important in resorption and remodeling of the extracellular matrix whose degradation may play a role in the villous atrophy characteristic of celiac disease (CD). We investigated the association between the polymorphism at position -1171 of the MMP-3 gene and susceptibility to CD in 225 Italian patients and 170 controls previously typed for human leukocyte antigen (HLA) class II genes. We also evaluated sex differences in the effect of this polymorphism on disease risk. A male-specific association of the 5A/6A polymorphism with CD was observed. The frequencies of 6A allele and 6A/6A genotype in affected male subjects were significantly above those observed both in male controls (p = 4.1 x 10(-3) and p = 3.4 x 10(-3); odds ratio = 2.4, 95% confidence interval 1.3-4.3) and in female patients (p = 2.7 x 10(-4) and p = 6.2 x 10(-4)). This is the first demonstration of a sex-specific association between the MMP-3 promoter polymorphism and CD. Homozygosity for the 6A allele appears as a risk factor for CD only in men, which is different from the HLA susceptibility alleles that confer a higher risk in women.