Oxidative stress is a key feature in the pathophysiology of sickle cell disease. Endurance training has been shown to reduce oxidative stress in the heart and the liver of sickle mice. However, the effects of endurance training on skeletal muscles, which are major producers of reactive oxygen species during exercise, are currently unknown. The aim of this study was to evaluate the effect of sickle genotype on prooxidant/antioxidant response to individualized endurance training in skeletal muscles of sickle mice. Healthy and homozygous Townes sickle mice were divided into trained or sedentary groups. Maximal aerobic speed and V̇O₂peak were determined using an incremental test on a treadmill. Trained mice ran at 40% to 60% of maximal aerobic speed, 1 h/day, 5 days/week for 8 weeks. Oxidative stress markers, prooxidant/antioxidant response, and citrate synthase enzyme activities were assessed in thegastrocnemius, in theplantaris, and in thesoleusmuscles. Maximal aerobic speed and V̇O₂peak were significantly reduced in sickle compared to healthy mice (-57% and -17%;p<0.001). NADPH oxidase, superoxide dismutase, and catalase activities significantly increased after training in thegastrocnemiusof sickle mice only. A similar trend was observed for citrate synthase activity in sickle mice (p=0.06). In this study, we showed an adaptive response to individualized endurance training on the prooxidant/antioxidant balance in thegastrocnemius,but neither in theplantarisnor in thesoleusof trained sickle mice, suggesting an effect of sickle genotype on skeletal muscle response to endurance treadmill training.