Background: The ongoing healthcare transforma on results in systems medicine and personalized care. This requires advanced interoperability scenarios. Objec ves: The paper aims at introducing a reference architecture model to enable the harmoniza on of exis ng and future specifi ca ons and standards. Methods: For enabling the harmoniza on of standards and specifi ca ons, they have to be correctly and formally represented using a system-theore cal, architecture-centric, ontology-based, policy-driven approach. Results: An Interoperability Reference Architecture Model has been developed and standardized at ISO TC 215 and CEN TC 251. It is used for re-engineering specifi ca ons and standards, that way enabling harmoniza on with any other specifi ca on. The proposed modeling methodology has also been introduced in several HL7 specifi ca ons. It is demonstrated by re-engineering the ISO 13606 reference model. Conclusion: The approach presented in the paper off ers a solu on for comprehensive interoperability at any interoperability level also including user domains and the individual user. That way, never-ending revision cycles and nego a on rounds for integra ng diff erent specifi ca ons in complex eHealth solu ons become obsolete.