BACKGROUND: Matrix metalloproteinase-2 (MMP-2) can degrade extracellular matrix and basement membrane, and play an important role in the development and progression of multiple carcinomas, including oral squamous cell carcinoma (OSCC). A -1306C→T polymorphism in the MMP-2 promoter disrupts SpI-binding site, and results in reduction of transcriptional activity. This study aimed to assess the association of such genotype with the risk of OSCC and oral submucous fibrosis (OSF), which is a precancerous condition that exhibits excessive collagen production and etiologically links to areca use. METHODS: Genomic DNA from the blood samples of 121 OSCC cases, 58 OSF cases and 147 controls were amplified by polymerase chain reaction (PCR) and subjected to denaturing high-performance liquid chromatography (dHPLC) analysis for genotyping. The OSCC were further classified into buccal squamous cell carcinoma (BSCC) and non-buccal squamous cell carcinoma (NBSCC), according to the site of involvement. Fisher's exact test and unconditional logistic regression models were used for statistical analysis. RESULTS: Subjects carrying CC genotype had nearly twofold increased risk for developing OSCC when comparing with CT or TT genotype. Subjects carrying CC genotype had more apparent risk (greater than fourfold) for developing NBSCC. However, no increase in risk for lymph node metastasis or advanced stage was identified in OSCC cases carrying such genotype. Preliminarily data suggest no significant association between subjects carrying CC genotype and the development of BSCC or OSF. CONCLUSION: This is the first paper demonstrating that functional genotype of MMP-2 promoter is a risk factor for oral carcinogenesis, particularly for the subsets occurring on non-buccal site.