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Background: Telemedicine is widely used but has uncertain value. We assessed telemedicine to further improve outcomes and reduce costs of comprehensive care (CC) for medically complex children., Methods: We conducted a single-center randomized clinical trial comparing telemedicine with CC relative to CC alone for medically complex children in reducing care days outside the home (clinic, emergency department, or hospital; primary outcome), rate of children developing serious illnesses (causing death, ICU admission, or hospital stay >7 days), and health system costs. We used intent-to-treat Bayesian analyses with neutral prior assuming no benefit. All participants received CC, which included 24/7 phone access to primary care providers (PCPs), low patient-to-PCP ratio, and hospital consultation from PCPs. The telemedicine group also received remote audiovisual communication with the PCPs., Results: Between August 22, 2018, and March 23, 2020, we randomly assigned 422 medically complex children (209 to CC with telemedicine and 213 to CC alone) before meeting predefined stopping rules. The probability of a reduction with CC with telemedicine versus CC alone was 99% for care days outside the home (12.94 vs 16.94 per child-year; Bayesian rate ratio, 0.80 [95% credible interval, 0.66-0.98]), 95% for rate of children with a serious illness (0.29 vs 0.62 per child-year; rate ratio, 0.68 [0.43-1.07]) and 91% for mean total health system costs (US$33 718 vs US$41 281 per child-year; Bayesian cost ratio, 0.85 [0.67-1.08])., Conclusion: The addition of telemedicine to CC likely reduced care days outside the home, serious illnesses, other adverse outcomes, and health care costs for medically complex children., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have no conflict of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)