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 moderate-intensity 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=0.038), oxidative enzyme activity [citrate synthase, p<0.001; β-hydroxyacyl-CoA dehydrogenase, p=0.009; type-I fiber cytochrome c oxidase, p=0.042; respiratory chain complex IV, p=0.017] and contents of respiratory chain complexes I (p=0.049), III (p=0.005), IV (p=0.003) and V (p=0.002). Respiratory frequency, respiratory exchange ratio, blood lactate concentration and rating of perceived exertion were all lower at a given submaximal power output after training versus non-training group (all p<0.05). 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. This article is protected by copyright. All rights reserved.