BACKGROUND: Sickle cell disease (SCD) is a chronic multisystem disorder associated with acute and chronic complications that may negatively impact the quality of life (QoL). The study aimed to assess the health-related QoL (HRQoL) of patients with SCD on hydroxyurea (HU) and the factors affecting HRQoL domains. MATERIALS AND METHODS: This case-control study included 174 patients with SCD (12–18-year-old); 87 were on HU for at least 1 year and 87 were not receiving HU. It also included 174 healthy adolescents of the same age group. The HRQoL was assessed using the Short Form 36 Health Survey version 2 (SF-36v2). A multivariate linear regression analysis was performed to assess the independent effect of studied variables on HRQoL dimensions. RESULTS: Patients with SCD who were not on HU were found to have significantly lower SF-36 v2 scores (all domains) compared to those on HU and control group, P < 0.001. While patients on HU had significantly lower SF-36 v2 scores in physical functioning, role physical (RP), general health, and physical health component score only compared to the control group, P < 0.001. Multivariate linear regression analysis revealed significant associations between duration of HU therapy and RP (R2 = 0.208, P = 0.021) and mental health component score (R2 = 0.389, P = 0.047) and between hemoglobin levels with social functioning (R2 = 0.370, P = 0.023). CONCLUSIONS: HU has improved the HRQoL of SCD patients, in almost all domains, in addition to the improvement in many disease-related complications, mainly painful episodes. The positive impact of HU on HRQoL was significantly associated with the duration of therapy.