Objective: To identify factors contributing to changes on quality, productivity, and safety outcomes during a large commercial electronic health record (EHR) implementation and to guide future research. Methods: We conducted a mixed-methods study assessing the impact of a commercial EHR implementation. The method consisted of a quantitative longitudinal evaluation followed by qualitative semi-structured, in-depth interviews with clinical employees from the same implementation. Fourteen interviews were recorded and transcribed. Three authors independently coded interview narratives and via consensus identified factors contributing to changes on 15 outcomes of quality, productivity, and safety. Results: We identified 14 factors that potentially affected the outcomes previously monitored. Our findings demonstrate that several factors related to the implementation (e.g., incomplete data migration), partially related (e.g., intentional decrease in volume of work), and not related (e.g., health insurance changes) may affect outcomes in different ways. Discussion: This is the first study to investigate factors contributing to changes on a broad set of quality, productivity, and safety outcomes during an EHR implementation guided by the results of a large longitudinal evaluation. The diversity of factors identified indicates that the need for organizational adaptation to take full advantage of new technologies is as important for health care as it is for other services sectors. Conclusions: We recommend continuous identification and monitoring of these factors in future evaluations to hopefully increase our understanding of the full impact of health information technology interventions.