BACKGROUND: Hydroxyurea reduces complications and improves health-related quality of life (HRQOL) in sickle cell disease (SCD) patients, however adherence remains suboptimal. Understanding patients' views of hydroxyurea is critical to optimize adherence, particularly in adolescents and young adults (AYA). Study objectives were to assess beliefs about hydroxyurea using the Beliefs about Medicines Questionnaire (BMQ), and to examine the relationship of patients' beliefs to their hydroxyurea adherence and HRQOL. METHODS: Thirty-four AYA with SCD participated in a cross-sectional study January-December 2015. Study assessments included BMQ to examine beliefs about hydroxyurea; Visual Analogue Scale (VAS) to assess hydroxyurea adherence; and Patient Reported Outcomes Measurement Information System (PROMIS(R)) to evaluate HRQOL. RESULTS: Participants (41% female, 91% Black) had median age of 13.5 (IQR 12-18) years. Participants' concerns about overuse of medications correlated with concerns about hydroxyurea (rs=0.36, p=0.04) and overall harm of medications (rs=0.5, p=0.003). Participants' age positively correlated with the necessity of hydroxyurea (rs=0.45, p=0.007). Participants' concerns about hydroxyurea and overuse of medications positively correlated with anxiety (rs=0.41, p=0.02; rs=0.44, p=0.01) and depression (rs=0.37, p=0.04; rs=0.54, p=0.001), but inversely correlated with peer relationships (rs=-0.45, p=0.03; rs=-0.44, p=0.03), respectively, suggesting better HRQOL with concerns. Fifty percent of participants reported low hydroxyurea adherence (VAS<80%), which was more seen in patients with higher concerns about hydroxyurea (p=0.02). CONCLUSIONS: Beliefs about hydroxyurea correlated with HRQOL scores and adherence levels. Addressing patients' concern about hydroxyurea and medications overall as well as routine assessment of adherence and beliefs could help to overcome adherence barriers.