In order to investigate the functions of the enzyme in melanoma, which accounts for less than 5% of all skin neoplasms but is responsible for most cutaneous malignancy-related deaths, shRNA-mediated gene silencing of PON2 was achieved in the A375 melanoma cell line and the effects on cell viability, proliferation, chemosensitivity, and ROS production were evaluated. This evidence concerns the gene PON2 and melanoma.