The increased application of eServices in health care, in general, and ePrescribing (electronic prescribing) in particular, have brought quality and interoperability to the forefront. The application of standards has been put forward as one important factor in improving interoperability. However, less focus has been placed on other factors, such as stakeholders' involvement and the measurement of interoperability. An information system (IS) can be regarded to comprise an instrument for technology-mediated work communication. In this study, interoperability refers to the interoperation in the ePrescribing process, involving people, systems, procedures and organizations. We have focused on the quality of the ePrescription message as one component of the interoperation in the ePrescribing process.The objective was to analyze how combined efforts in improving interoperability with the introduction of the new national ePrescription format (NEF) have impacted interoperability in the ePrescribing process in Sweden, with the focus on the quality of the ePrescription message.Consecutive sampling of electronic prescriptions in Sweden before and after the introduction of NEF was undertaken in April 2008 (pre-NEF) and April 2009 (post-NEF). Interoperability problems were identified and classified based on message format specifications and prescription rules.The introduction of NEF improved the interoperability of ePrescriptions substantially. In the pre-NEF sample, a total of 98.6% of the prescriptions had errors. In the post-NEF sample, only 0.9% of the prescriptions had errors. The mean number of errors was fewer for the erroneous prescriptions: 4.8 in pre-NEF compared to 1.0 in post-NEF.We conclude that a systematic comprehensive work on interoperability, covering technical, semantical, professional, judicial and process aspects, involving the stakeholders, resulted in an improved interoperability of ePrescriptions.