Background Understanding the genetic and molecular pathophysiology of lymphedema contributes to the identification of the complex interaction of genes associated with lymphedema and provides a key therapeutic opportunity to restore lymphatic function. This study aims to answer whether the single-nucleotide polymorphism (SNP) rs1030868 in the MMP-2 gene could be an associated variant in lymphedema development. Methods This study was carried out on 93 lymphedema cases (patients’ group) and 187 healthy individuals (control group). Genotyping of MMP-2 (rs1030868) was done following the protocol of Custom TaqMan® SNP Genotyping Assays. TaqMan™ Fast Advanced Master Mix (Cat# 4448892) was used. Results The risk alleles for MMP-2 SNP rs1030868 were A and G of lymphedema development. The GG genotype was associated with triple the risk of lymphedema (OR 3.2, 95% CI 1.2–6.5, p = 0.019), while the AA genotype was associated with 5.9 times the likelihood of lymphedema (OR 5.9, 95% CI 2.3–11.9, p < 0.001). Conclusions We concluded that the single-nucleotide polymorphisms of rs1030868 in the matrix metallopeptidase 2 gene (allele A and allele G) could be associated variants with the development of lymphedema.