In the past 2 decades, the United States has seen widespread adoption of electronic health records (EHRs) and a transition from mostly locally developed EHRs to commercial systems. However, most research on quality improvement and safety interventions in EHRs is still conducted at a single site, in a single EHR. Although single-site studies are important early in the innovation lifecycle, multisite studies of EHR interventions are critical for generalizability. Because EHR software, configuration, and local context differ considerably across health care organizations, it can be difficult to implement a single, standardized intervention across multiple sites in a study. This article outlines key strengths, weaknesses, challenges, and opportunities for standardization of EHR interventions in multisite studies and describes flexible trial designs suitable for studying complex interventions, including EHR interventions. It also outlines key considerations for reporting on flexible trials of EHR interventions, including sharing details of the process for designing interventions and their content, details of outcomes being studied and approaches for pooling, and the importance of sharing code and configuration whenever possible.