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Objective The aim of this work was to study the relations hip between matrix metalloproteinase-1 (MMP-1) −1607 1G/2G gene polymorphism and hepatocellular carcinoma (HCC) in patients infected with hepatitis B or C viruses. Background MMP-1, an interstitial collagenase, plays an important role in the breakdown of extracellular matrix. It has been demonstrated that the overexpression of this enzyme is associated with tumor initiation, invasion, and metastasis. The − 1607 single guanine (1G)-to-2G polymorphism (reference single-nucleotide polymorphism 1799750) in the MMP-1 promoter region creates an E26 (Ets)-binding site and results in transcriptional upregulation. Therefore, the MMP-1 polymorphism may influence an individual's susceptibility to the development of certain tumors such as HCC. Patients and methods This study was carried out on 100 participants; 40 of them were patients with HCC infected with hepatitis C virus, 20 of them were patients with HCC infected with hepatitis B virus, and the remaining 40 were age-matched and sex-matched healthy volunteers. All participants were subjected to full history taking, laboratory investigations including liver profile, α-fetoprotein, and prothrombin induced by vitamin K absence II, and determination of MMP-1 − 1607 1G/2G polymorphism by PCR–restriction fragment length polymorphism assay. Results The MMP-1 − 1607 genotype distribution among HCC patients was significantly different from that in healthy controls (P < 0.001). Compared with the wild-type 1G/1G genotype, the variant 1G/2G and 2G/2G genotypes and the 2G allele were associated with risk for HCC (P < 0.001). The 1G/2G genotype was associated with large tumor size. The 1G/2G and 2G/2G genotypes were associated with Child–Pugh B and C. The 1G/2G genotype was associated with advanced tumor stage and the 2G/2G genotype was associated with metastatic tumor stage. Conclusion The results suggest that the MMP-1 − 1607 1G/2G polymorphism is associated with an increased risk for HCC.