© 2021Background: Low levels of antioxidant paraoxonase 1 (PON1) enzyme activity, PON1–Q192R polymorphism (a glutamine (Q) to arginine (R) substitution at position 192), PON1–L55M polymorphism (a leucine (L) to methionine (M) substitution at position 55), and oxidized low-density lipoprotein (oxLDL) are risk factors for coronary heart disease. Aerobic exercise improves PON1 activity, but the effects of hypoxic exercise are yet unclear. The aim of this study was to determine the effects of hypoxic underwater rugby training on PON1 activity and oxLDL levels and the role of the mentioned polymorphisms. Methods: Serum PON1 and arylesterase activities (ARE), PON1, PON3, and oxLDL protein levels (by using the enzyme-linked immunosorbent assays) were determined in an athletic group (42 trained male underwater rugby players; age = 21.7 ± 4.2 years, mean ± SD) and a control group (43 sedentary men; age = 23.9 ± 3.2 years). The polymorphisms were determined from genomic DNA samples. Results: PON1 activity (25.1%, p = 0.052), PON3 (p < 0.001), and oxLDL (p < 0.001) of the athletic group, including most genotype groups, were higher than those of the control group. In comparison to the controls, PON1 activity levels (p = 0.005) of the PON1–Q192R homozygote QQ genotype group and PON1 activity levels (30%, p = 0.116) of the PON1–L55M homozygote LL genotype group were higher, whereas ARE activity values of athletic R allele carrier (Rc = QR + RR) (p = 0.005) and LL group (p = 0.002) were lower than the control genotype groups related to their polymorphisms. Conclusions: Hypoxic training can cause (1) significant oxidative stress, including oxLDL, and an antioxidant response (increase in PON1 activity and PON3), (2) differences in the activity of PON1 and ARE, which are modified by PON1–Q192R and PON1–L55M polymorphisms, respectively, and (3) improvements in PON1 activity of QQ and LL groups. However, hypoxic training can cause a disadvantage of LL and Rc groups for ARE.