We aim to explore the associations between matrix metalloproteinase (MMP) MMP-2/MMP-9 gene polymorphism with ulinastatin (UTI) efficacy in treating severe acute pancreatitis (SAP). A total of 276 SAP patients were assigned into the control (n=135) and observation (n=141) groups. PCR-restriction fragment length polymorphism (PCR-RFLP) was used for genotype and allele frequency distribution. Relevance of MMP-2/MMP-9 genotypes with UTI efficacy was analyzed. The observation group showed lowered duration in symptoms (abdominal distension, abdominal pain, tenderness, and rebound tenderness) than the control group. Laboratory analysis (serum calcium, white blood cells, serum amylase, urine amylase, APACHE-II, and Balthazar CTIS scores) were decreased, while serum albumin levels increased after 7th day of therapy. The total effective rate of UTI for patients with MMP-2 C-1306T C/C genotype was higher than those with C/T and T/T genotypes after the 7th day of therapy, which was lower in patients with MMP-9 C-1562T C/C and C/T genotypes than those with T/T genotype. The duration for symptoms in patients with MMP-9 C-1562T T/T genotype was shorter than those with C/C and C/T genotypes, which was less in patients with MMP-2 C-1306T C/C genotype than those with C/T and T/T genotypes. The improvement values of APACHE-II and Balthazar CTIS scores for patients with MMP-2 C-1306T C/C genotype were higher than those with C/T and T/T genotypes, which for patients with MMP-9 C-1562T C/C and C/T genotypes were lower than those with T/T genotype. These results demonstrated that MMP-2/MMP-9 gene polymorphism was associated with UTI efficacy for SAP.