BACKGROUND: Electronic personal health records (ePHRs) are defined as electronic applications through which individuals can access, manage, and share health information in a private, secure, and confidential environment. Existing evidence shows their benefits in improving outcomes, especially for chronic disease patients. However, their use has not been as widespread as expected partly due to barriers faced in their adoption and use. We aimed to identify the types of barriers to a patient, provider, and caregiver adoption/use of ePHRs and to analyze their extent in chronic disease care. METHODS: A systematic search in Medline, PubMed, Science Direct, Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Central Register of Controlled Trials, and the Institute of Electrical and Electronics Engineers (IEEE) database was performed to find original studies assessing barriers to ePHR adoption/use in chronic care until the end of 2018. Two researchers independently screened and extracted data. We used the PHR adoption model and the Unified Theory of Acceptance and Use of Technology to analyze the results. The Mixed Methods Appraisal Tool (MMAT) version 2018 was used to assess the quality of evidence in the included studies. RESULTS: Sixty publications met our inclusion criteria. Issues found hindering ePHR adoption/use in chronic disease care were associated with demographic factors (e.g., patient age and gender) along with key variables related to health status, computer literacy, preferences for direct communication, and patient's strategy for coping with a chronic condition; as well as factors related to medical practice/environment (e.g., providers' lack of interest or resistance to adopting ePHRs due to workload, lack of reimbursement, and lack of user training); technological (e.g., concerns over privacy and security, interoperability with electronic health record systems, and lack of customized features for chronic conditions); and chronic disease characteristics (e.g., multiplicities of co-morbid conditions, settings, and providers involved in chronic care). CONCLUSIONS: ePHRs can be meaningfully used in chronic disease care if they are implemented as a component of comprehensive care models specifically developed for this care. Our results provide insight into hurdles and barriers mitigating ePHR adoption/use in chronic disease care. A deeper understating of the interplay between these barriers will provide opportunities that can lead to an enhanced ePHR adoption/use.