As the availability of interoperable electronic health records (iEHRs) or health information exchanges (HIEs) continues to increase, there is greater need and opportunity to assess the current evidence base on what works and what does not regarding the adoption, use, and impact of iEHRs.The purpose of this project is to assess the international evidence base on the adoption, use, and impact of iEHRs.We conducted a systematic review, searching multiple databases-MEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL)-with supplemental searches conducted in Google Scholar and grey literature sources (ie, Google, Grey Literature Report, and OpenGrey). All searches were conducted in January and February 2017. Articles were eligible for inclusion if they were published in English, were published from 2006 to 2017, and were either an original research study or a literature review. In order to be included, articles needed to focus on iEHRs and HIEs across multiple health care settings, as well as on the impact and effectiveness of iEHR adoption and use.We included 130 articles in the synthesis (113 primary studies, 86.9%; 17 reviews, 13.1%), with the majority focused on the United States (88/130, 67.7%). The primary studies focused on a wide range of health care settings; the three most prevalent settings studied included acute care (59/113, 52.2%), primary care (44/113, 38.9%), and emergency departments (34/113, 30.1%). We identified 29 distinct measurement items in the 113 primary studies that were linked to 522 specific measurement outcomes. Productivity and quality were the two evaluation dimensions that received the most attention, accounting for 14 of 29 (48%) measurement items and 306 of 522 (58.6%) measurement outcomes identified. Overall, the majority of the 522 measurement outcomes were positive (298/522, 57.1%). We also identified 17 reviews on iEHR use and impact, 6 (35%) that focused on barriers and facilitators to adoption and implementation and 11 (65%) that focused on benefits and impacts, with the more recent reviews finding little generalizable evidence of benefit and impact.This review captures the status of an evolving and active field focused on the use and impact of iEHRs. While the overall findings suggest many positive impacts, the quality of the primary studies were not evaluated systematically. When broken down by specific measurement item, the results directed attention both to measurement outcomes that were consistently positive and others that were mostly negative or equivocal.