Background: Complications related to sickle cell disease (SCD) result in significant declines in health-related quality of life (HRQOL). While hydroxyurea reduces SCD complications, adherence remains suboptimal. The study's objectives were to assess the feasibility of Internet-based electronic assessment of HRQOL in SCD clinic and to examine the relationship between HRQOL and hydroxyurea adherence in adolescents and young adults (AYAs) with SCD. Procedure: A cross-sectional survey was administered on tablets to 34 AYAs (12-22 years old) in a SCD clinic from January through December 2015. Study measures included Patient Reported Outcomes Measurement Information System (PROMIS (R)) computerized adaptive testing and (c) Modified Morisky Adherence Scale 8-items ((c) MMAS-8). Results: Participants (59% male, 91% Black) had median age of 13.5 (range 12-18) years. Ninety-one percent completed PROMIS (R) measures electronically in the clinic, meeting our feasibility criterion of >= 85% completion rate. (c) MMAS-8 scores positively correlated with fetal hemoglobin (HbF) (r(s) = 0.34, P = 0.04) and mean corpuscular volume (MCV) (r(s) = 0.42, P = 0.01) and inversely correlated with fatigue (r(s) = -0.45, P = 0.01), depression (r(s) = -0.3, P = 0.08), and social isolation (r(s) = -0.78, P = 0.02). Low (c) MMAS-8 scores, indicating poor adherence, were associated with worse fatigue (P = 0.001) and trended toward significance for pain (P = 0.07) and depression (P = 0.06). Homozygous hemoglobin S disease patients with low HbF (< 16%) had worse social isolation (P = 0.04) and those with low MCV (< 102 fl) reported worse fatigue (P = 0.001), pain (P = 0.01), mobility (P = 0.01), and social isolation (P = 0.04). Conclusions: HRQOL assessment in the SCD clinic is feasible. SCD patients with low hydroxyurea adherence and/or low HbF or MCV levels had worse HRQOL scores, particularly fatigue. Future prospective studies examining the relationship between HRQOL and hydroxyurea adherence are warranted.