Sickle cell disease (SCD) is a monogenic disease caused by mutations in the β-globin gene. The complications related to the disease are systemic as they impact multiple organ systems. Our goal in this study was to identify metabolome changes contributing to SCD-related severity. Employing both targeted and untargeted approaches, we profiled the plasma of 706 SCD patients using liquid chromatography tandem mass spectrometry. The cohort included 406 French patients of recent African descent and 300 African Americans from the southeastern US. We started analysis networks of metabolites after being able to harmonize the entire metabolomics dataset.