Purpose: The matrix metalloproteinases (MMPs) are postulated to be involved in the development of retinal angiogenesis through the regulation of extracellular matrix. The objective of the present study was to test for a possible association of five single nucleotide polymorphisms (SNPs) in the MMP-2 gene and two polymorphisms in the MMP-9 gene with proliferative diabetic retinopathy (PDR) and to determine their plasma levels. Methods: Genotypes were detected by polymerase chain reactions followed by restriction analyses with specific endonucleases and their frequencies determined in a study comprising three groups of Caucasian subjects (total n=490, diabetics with and without PDR and non-diabetics). The plasma levels of the MMP-2 and -9 proteins were analyzed by ELISA. Results: Neither MMP-2 nor MMP-9 SNPs revealed significant association with PDR in single-locus comparisons; similarly, MMP-2 haplotype frequencies did not differed significantly between groups. Both MMP-2 and MMP-9 plasma levels showed statistically significant differences among the studied groups (p<0.001 and p=0.001, respectively) with highest levels in the PDR group. MMP-2 plasma levels were significantly higher in carriers of either the -1306CC and CT genotypes (p=0.009) or CGCG haplotype (p=0.043). Conclusions: These findings indicate that genotype- and haplotype-specific effects on the MMP-2 gene expression corresponding with its plasma levels may contribute to the susceptibility to PDR.