It has been shown that the A16 variant allows a 30–40% more efficient targeting of MnSOD to the mitochondria than V16 and therefore is associated with high levels of mitochondrial concentration and activity . In this study we observed higher levels of oxidative stress before and after exercise in athletes bearing the mutated allele V16, either in heterozygosis or in homozygosis, than in wild-type subjects, as shown by increased dROMs and AOPP and decreased BAP and free thiols. However, the differences with wild-type subjects were found to be significant only for variations of AOPP plasma levels. Differences in SOD2 A16V genetic background did neither affect plasma SOD activity nor affect CAT or GPx activities. This could be explained taking into account the fact that SOD2 represents the primary level of antioxidant defense in cellular mitochondria. Instead, the SOD2 A16V polymorphism represents a risk factor for increased muscle injury in water polo players, since athletes bearing the homozygous mutated VV16 genotype exhibited higher values of LDH, CK, CK-MB, troponin, and myoglobin than wild-type AA and heterozygous AV subjects, even if these differences were not always significant likely due to the small size of genotype subgroups.