The aim of the study was to analyze the effect of SOD2 Val16Ala polymorphism on blood biochemical response to chronic swimming training. Healthy men (students of physical education) participated in a swimming training program (ST group) or served as a control group (CON group). The swimming training program lasted 12 weeks (1.5 h per day; 4 days per week). Fasting blood samples were obtained prior to (pre) and after (post) a 12-week study period, to measure the biomarkers of oxidative stress, muscle damage and lipid profile. No significant changes in the study parameters were documented in CON group after a 12-week study period, either overall or among carriers of specific SOD2 Val16Ala genotypes. In ST group, post-training decrease in serum lipid hydroperoxides (p < 0.05) and creatine kinase activity (p < 0.05) was associated with Ala/Ala genotype of SOD2 Val16Ala polymorphism. In turn, the increase in serum activity of superoxide dismutase (p < 0.05) was associated with Val carriers, and Val/Val genotype additionally predisposed to the post-training increase in total glutathione level in whole blood (p < 0.05). Moreover, in ST group, a 12-week swimming training program induced an increase in serum concentration of total cholesterol (p < 0.05), which resulted from an increase in both high density (p < 0.05) and low density lipoprotein cholesterol (p < 0.05). The change in high density lipoprotein cholesterol level was irrespective of the genotype. Also, a tendency to post-training increase in both total and low density lipoprotein cholesterol was observed in all three genotypes, although these changes were significant solely in Ala/Val genotype carriers (p < 0.05). In conclusion, 12-week swimming training induces changes in oxidative stress and muscle damage parameters, as well as in lipid profile. These changes seem to be associated with the presence of SOD2 Val16Ala polymorphism. Presence of Ala allele, especially as homozygote, is associated with some beneficial post-training changes, such as a decrease in lipid peroxidation and less pronounced muscle damage. In turn, the influence of SOD2 Val16Ala polymorphism on the changes in lipid profile in response to chronic swimming training should be verified in further study.