Oxidant stress and overproduction of reactive oxygen species (ROS) contribute to the development of cardiovascular disease. Oxidative modifications of low-density lipoproteins (LDL) are thought to play an early and critical role in atherogenesis. LDL oxidation can be reproduced in vitro, but results usually show a large interindividual variation not entirely explained by the environment. Free radical-induced hemolysis is also proposed to reveal the overall antioxidant capacity. The roles of genetic factors and exercise on the variability of both measures were investigated. The study was conducted in 146 healthy individuals from 28 families participating in a 20-week exercise-training program. In addition to important biological and environmental influences on variation, significant familial aggregation was detected in all oxidation measures. Exercise did not significantly modify the LDL oxidation parameters, but significantly increased resistance was observed in the free radical-induced hemolysis, especially in women, this effect was not observed in smokers. In total, the findings suggest the presence of familial effects in the response to ex vivo oxidation. Further, smoking negates the beneficial effect of exercise training on erythrocyte resistance to free radical-induced hemolysis. These observations emphasize the importance of context in the evaluation of exercise and oxidant stress.