This article analyzes the range of system optimization activities taking place over an extended period following the implementation of computerized physician order entry and clinical decision support systems. We undertook 207 qualitative semi-structured interviews, 24 rounds of non-participant observations of meetings and system use, and collected 17 organizational documents in five hospitals over three time periods between 2011 and 2016. We developed a systematic analysis of system optimization activities with eight sub-categories grouped into three main categories. This delineates the range of system optimization activities including resolving misalignments between technology and clinical practices, enhancing the adopted system, and improving user capabilities to utilize/further optimize systems. This study highlights the optimization efforts by user organizations adopting multi-user, organization-spanning information technologies. Hospitals must continue to attend to change management for an extended period (up to 5 years post-implementation) and develop a strategy for long-term system optimization including sustained user engagement, training, and broader capability development to ensure smoother and quicker realization of benefits.