The matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) have been shown to play important roles in multiple ways in all stages of cancer initiation and development. Single nucleotide polymorphisms identified in the promoters of MMP2 (-1306C-->T) and TIMP2 (-418G-->C) abolish the Sp1-binding site and thus may down-regulate expression of the genes. This case-control study examined the contribution of these functional polymorphisms to susceptibility to development and metastasis of breast cancer. MMP2 genotypes were determined by PCR-based denaturing high performance liquid chromatography analysis and TIMP2 genotypes identified by a PCR-RFLP method in 462 breast cancer patients and 509 frequency matched control women. We found that the variant MMP2 genotype (-1306CT or TT) was associated with substantially reduced risk of breast cancer [odds ratio (OR), 0.46; 95% confidence interval (95% CI), 0.34-0.63], compared with the CC genotype. For TIMP2, a moderately reduced risk of the cancer (OR, 0.76; 95% CI, 0.58-0.99) was also associated with the variant allele (-418GC or CC), compared with the GG common allele. Furthermore, it seemed that the polymorphisms in the two genes had some additive effect and the reduced risk related to the polymorphisms appeared to be more pronounced in younger subjects. However, no significant associations were observed between the polymorphisms in the two genes and tumor stage and metastasis of the cancer at the time of diagnosis. These findings suggest that the presence of the variant allele in the promoter of MMP2 or TIMP2 may be a protective factor for the development of breast cancer.