BACKGROUND/AIM: Renal cell carcinoma (RCC) accounts for more than 90% of kidney malignancies worldwide. Matrix metalloproteinase-2 (MMP-2) has been reported to be dysregulated in multiple cancers. However, the relationship between MMP-2 genetic polymorphisms and RCC risk has rarely been investigated. This study aimed to evaluate the associations of two promoter polymorphisms, MMP-2 rs243865 and rs2285053, with RCC susceptibility in a Taiwanese population. MATERIALS AND METHODS: A hospital-based case-control study was conducted including 118 RCC patients and 590 cancer-free controls. Genotyping of MMP-2 rs243865 and rs2285053 was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: A significant association was observed between MMP-2 rs243865 and RCC susceptibility (p for trend=0.0077). Compared to the CC genotype, individuals carrying the TT genotype exhibited a markedly increased risk of RCC (OR=4.29, 95%CI=1.56-11.83, p=0.0069), whereas the CT genotype showed no significant effect (OR=1.31, 95%CI=0.80-2.16, p=0.3530). The T allele was also associated with elevated RCC risk (OR=1.71, 95%CI=1.15-2.54, p=0.0101). In contrast, rs2285053 showed no significant association with RCC. Stratified analyses revealed significant MMP-2 rs243865 genotype differences among subgroups defined by smoking, alcohol consumption, and hypertension status (p=0.0175, 0.0173, and 0.0063, respectively). CONCLUSION: MMP-2 rs243865, particularly the TT genotype, may serve as a genetic susceptibility marker for RCC and may interact with lifestyle and clinical factors including smoking, alcohol drinking, and hypertension. Further large-scale studies are warranted to validate these observations and clarify the biological mechanisms underlying MMP-2-mediated RCC carcinogenesis.