Abstract This study analyzed the association of functionally significant SNPs of matrix metalloproteinase ( MMP ) genes in the development of peptic ulcer disease (PUD) in Caucasians from Central Russia. Ten SNPs of the MMP-1, MMP-2, MMP-3, MMP-8 , and MMP-9 genes were analyzed for association with PUD in a cohort of 798 patients with PUD (including 404 H. pylori -positive and 394 H. pylori -negative) and 347 H. pylori -negative controls using logistic regression and assuming the additive, recessive, and dominant genetic models. The variants of MMP-1 , MMP-2 , MMP-3 , and MMP-8 did not manifest any significant associations with the diseases. Five SNPs of the MMP-9 gene demonstrated such association. Allele G of the rs17576 MMP-9 locus conferred a higher risk for PUD (OR adj  = 1.31, p perm  = 0.016), haplotype AACG of loci rs17576-rs3787268-rs2250889-rs17577 of the MMP-9 gene decreased risk for PUD (OR adj  = 0.17, p perm  = 0.003). Also, allele C of rs3918249, allele G of rs17576 and haplotype CG of rs3918249-rs17576 of the MMP-9 gene increased risk for H. pylori -positive PUD (OR adj  = 1.82, p perm  = 0.002; OR adj  = 1.53–1.95 p perm  = 0.001–0.013 and OR adj  = 1.49 p perm  = 0.009 respectively). The above loci and 50 linked to them possess significant regulatory effects and may affect the alternative splicing of four genes and the expression of 17 genes in various organs and tissues related to the PUD pathogenesis.