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) (rs = 0.34, P = 0.04) and mean corpuscular volume (MCV) (rs = 0.42, P = 0.01) and inversely correlated with fatigue (rs = -0.45, P = 0.01), depression (rs = -0.3, P = 0.08), and social isolation (rs = -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.