Given the limited literature data available on oxidative stress response in water polo, we first investigated changes in oxidative stress biomarkers and antioxidant potential after a regular training program in a group of water polo male players. Moreover, we aimed to assess the effects of genetic background on oxidative response, with particular regard to the role played by single nucleotide polymorphisms (SNP) A16V of SOD2, encoding for intracellular Mn-SOD, −844 G>A of CAT, and rs1800668 of GPx-1.