ABSTRACT: BACKGROUND:Pediatric medical conditions have the potential to result in challenging psychological symptoms (eg, anxiety, depression, and posttraumatic stress symptoms [PTSS]) and impaired health-related quality of life in youth. Thus, effective and accessible interventions are needed to prevent and treat psychological sequelae associated with pediatric medical conditions. Electronic health (eHealth) interventions may help to meet this need, with the capacity to reach more children and families than in-person interventions. Many of these interventions are in their infancy, and we do not yet know what key components contribute to successful eHealth interventions. OBJECTIVE:The primary objective of this study was to conduct a systematic review to summarize current evidence on the efficacy of eHealth interventions designed to prevent or treat psychological sequelae in youth with medical conditions. METHODS:MEDLINE (PubMed) and PsycINFO databases were searched for studies published between January 1, 1998, and March 1, 2019, using predefined search terms. A total of 2 authors independently reviewed titles and abstracts of search results to determine which studies were eligible for full-text review. Reference lists of studies meeting eligibility criteria were reviewed. If the title of a reference suggested that it might be relevant for this review, the full manuscript was reviewed for inclusion. Inclusion criteria required that eligible studies (1) had conducted empirical research on the efficacy of a Web-based intervention for youth with a medical condition, (2) had included a randomized trial as part of the study method, (3) had assessed the outcomes of psychological sequelae (ie, PTSS, anxiety, depression, internalizing symptoms, or quality of life) in youth (aged 0-18 years), their caregivers, or both, (4) had included assessments at 2 or more time points, and (5) were available in English language. RESULTS:A total of 1512 studies were reviewed for inclusion based on their title and abstracts; 39 articles qualified for full-text review. Moreover, 22 studies met inclusion criteria for the systematic review. Of the 22 included studies, 13 reported results indicating that eHealth interventions significantly improved at least one component of psychological sequelae in participants. Common characteristics among interventions that showed an effect included content on problem solving, education, communication, and behavior management. Studies most commonly reported on child and caregiver depression, followed by child PTSS and caregiver anxiety. CONCLUSIONS:Previous research is mixed but suggests that eHealth interventions may be helpful in alleviating or preventing problematic psychological sequelae in youth with medical conditions and their caregivers. Additional research is needed to advance understanding of the most powerful intervention components and to determine when and how to best disseminate eHealth interventions, with the goal of extending the current reach of psychological interventions.