Health Information Systems (HISs) are expected to have a positive impact on quality and efficiency of health care. Rapid investment in and diffusion of HISs has increased the importance of monitoring the adoption and impacts of them in order to learn from the initiatives, and to provide decision makers evidence on the role of HISs in improving health care. However, reliable and comparable data across initiatives in various countries are rarely available. A four-phase approach is used to compare different HIS indicator methodologies in order to move ahead in defining HIS indicators for monitoring effects of HIS on health care performance. Assessed approaches are strong on different aspects, which provide some opportunities for learning across them but also some challenges. As yet, all of the approaches do not define goals for monitoring formally. Most focus on health care structural and process indicators (HIS availability and intensity of use). However, many approaches are generic in description of HIS functionalities and context as well as their impact mechanisms on health care for HIS benchmarking. The conclusion is that, though structural and process indicators of HIS interventions are prerequisites for monitoring HIS impacts on health care outputs and outcomes, more explicit definition is needed of HIS contexts, goals, functionalities and their impact mechanisms in order to move towards common process and outcome indicators. A bottom-up-approach (participation of users) could improve development and use of context-sensitive HIS indicators.