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Hydroxyurea reduces sickle cell disease (SCD) complications, but medication adherence is low. We tested two mobile health (mHealth) interventions targeting determinants of low adherence among patients (InCharge Health) and low prescribing among providers (HU Toolbox) in a multi-center non-randomized trial of individuals with SCD ages 15-45. We compared the percentage of days covered (PDC), labs, healthcare utilization, and self-reported pain over 24 weeks of intervention and 12 weeks post-study with a 24-week pre-intervention interval. We enrolled 293 patients (51% male; median age 27.5 years, 86.8% HbSS/HbSß0-thalassemia). The mean change in PDC among 235 evaluable subjects increased (39.7% to 56.0%; p<0.001) and sustained (39.7% to 51.4%, p<0.001). Mean HbF increased (10.95% to 12.78%; p=0.03). Self-reported pain frequency fell (3.54 to 3.35 events/year; p=0.041). InCharge Health was used >or=1 day by 199 of 235 participants (84.7% implementation; median usage: 17% study days; IQR: 4.8-45.8%). For individuals with >or=1 baseline admission for pain, admissions per 24 weeks declined from baseline through 24 weeks (1.97 to 1.48 events/patient, p=0.0045) and weeks 25-36 (1.25 events/patient, p=0.0015). PDC increased with app use(p<0.001), with the greatest effect in those with private insurance (p=0.0078), in older subjects (p=0.033), and those with lower pain interference (p=0.0012). Of the 89 providers (49 hematologists, 36 advanced care providers, four unreported), only 11.2% used HU Toolbox >or=1/month on average. This use did not affect change in PDC. Tailoring mHealth solutions to address barriers to hydroxyurea adherence has the potential to improve adherence and provide clinical benefits. A definitive randomized study is warranted.