Policy makers and health system managers in many countries are advocating the deployment of inter-operable health information technology systems, spanning organisations in a health economy, believing that they will be clinically effective. The case for investments has not, however, been made to date. This paper presents early results from a systematic review of the effects of inter-operable systems on patient safety. The review uses the realist synthesis method, which focuses on evidence about the decisions and actions that link interventions and outcomes, as well as the evidence about those outcomes. The evidence base is sufficient to identify plausible arguments for investments in inter-operable systems. This said, there is limited empirical evidence about each of the steps in the sequences of events. We comment on implications for the design of sustainable socio-technical solutions. We suggest that current gaps in the evidence base are in areas where informatics field methods can make a valuable contribution to our understanding of the role of inter-operable systems in patient safety.