Sickle cell disease (SCD) patients display skeletal muscle hypotrophy, altered oxidative capacity, exercise intolerance and poor quality of life. We previously demonstrated that moderate-intensity endurance training is beneficial for improving muscle function and quality of life of patients. The present study evaluated the effects of this moderate-intensity endurance training program on skeletal muscle structural and metabolic properties. Of the 40 randomized SCD patients, complete data sets were obtained from 33. The training group (n = 15) followed a personalized moderateintensity endurance training program, while the non-training (n = 18) group maintained a normal lifestyle. Biopsies of the vastus lateralis muscle and submaximal incremental cycling tests were performed before and after the training program. Endurance training increased type I muscle fiber surface area (P = .038), oxidative enzyme activity [citrate synthase, P < .001; β-hydroxyacyl-CoA dehydrogenase, P = .009; type-I fiber cytochrome c oxidase, P = .042; respiratory chain complex IV, P = .017] and contents of respiratory chain complexes I (P = .049), III (P = .005), IV (P = .003) and V (P = .002). Respiratory frequency, respiratory exchange ratio, blood lactate concentration and rating of perceived exertion were all lower at a given submaximal power output after training vs non-training group (all P < .05). The muscle content of proteins involved in glucose transport and pH regulation were unchanged in the training group relative to the non-training group. The moderate-intensity endurance exercise program improved exercise capacity and muscle structural and oxidative properties. This trial was registered at www.clinicaltrials.gov as #NCT02571088. 1 | INTRODUCTION Sickle cell disease (SCD) is the most frequent worldwide genetic disease. 1 This hemoglobinopathy results in synthesis of abnormal S hemoglobin (HbS) which may polymerize once deoxygenated, potentially resulting in the sickling of red blood cells (RBC). Sickle-shaped RBC are less deformable and adhere better to endothelium, 1 the combination of which may cause sickle RBC entrapment in the microcirculation. Entrapment of RBC may progress to painful vaso-occlusive crises (VOC), one of the main complications of the disease, 1 and may lead to failure of vital organs. 2 Sickle RBC are also fragile, causing hemolysis, release of free hemoglobin into circulation and severe chronic anemia. 1 SCD patients are often subjected to arterial †EXDRE collaborative study group