Background & Aims: Sickle cell disease (SCD has a worldwide distribution and causes significant morbidity and mortality in children and adults. Few studies addressed the determinants of SCD severity in adults; therefore, we investigated the impact of nutrition on the outcome of SCD and health-related quality of life (HRQoL) in adult patients, Methods: In this longitudinal study, we recruited and prospectively followed 62 adults with SCD  (aged ?18 years) for a  median of 93 months. At entry and follow-up, patients provided medical and dietary history,  had a physical examination and anthropometric measurements, assessment of protein-energy intake, measurement of micronutrient levels, estimation of  SCD severity score, and determination of the HRQoL  (SF-26v2). The study outcome was a composite of hospitalization due to SCD crises or death. Results: At baseline, 42 (67.74%) patients had macro and, or micro-undernutrition (Group A), and 20 (32.26%) were well nourished. (Group B).  The   BMI and most anthropometric measurements were significantly lower in SCD patients compared to control subjects.  In several SCD patients, undernutrition resulted from reduced food intake and reduced absorption due to concomitant gastrointestinal disorders. Seventy percent of  SCD patients had vitamin D,  vitamin B12, and zinc deficiencies. Under-nourished patients had significantly higher SCD severity scores, frequent SCD related hospitalizations, higher mortality rates, and reduced HRQoL compared to well-nourished patients.  Protein-energy and micronutrient deficiencies were independent predictors of severe SCD and mortality. Correction of undernutrition and hydroxyurea therapy improved SCD severity scores and HRQoL. Conclusion: Patients with sickle cell disease have various degrees of macro and micro deficiencies, which increase SCD severity and hospitalizations and reduce the health-related quality of life. Early diagnosis and prompt correction of macro and micronutrient deficiencies need to be incorporated in the standard of care of SCD patients to improve the disease outcomes.