INTRODUCTION: The Electronic Health Records for Clinical Research (EHR4CR) technological platform has been developed to enable the trustworthy reuse of hospital electronic health records data for clinical research. The EHR4CR platform can enhance and speed up clinical research scenarios: protocol feasibility assessment, patient identification for recruitment in clinical trials, and clinical data exchange, including for reporting serious adverse events. Our objective was to seed a multi-stakeholder ecosystem to enable the scalable exploitation of the EHR4CR platform in Europe, and to assess its economic sustainability. MATERIALS AND METHODS: Market analyses were conducted by a multidisciplinary task force to define an EHR4CR emerging ecosystem and multi-stakeholder value chain. This involved mapping stakeholder groups and defining their unmet needs, incentives, potential barriers for adopting innovative solutions, roles and interdependencies. A comprehensive business model, value propositions, and sustainability strategies were developed accordingly. Using simulation modelling (including Monte Carlo simulations) and a 5-year horizon, the potential financial outcomes of the business model were forecasted from the perspective of an EHR4CR service provider. RESULTS: A business ecosystem was defined to leverage the EHR4CR multi-stakeholder value chain. Value propositions were developed describing the expected benefits of EHR4CR solutions for all stakeholders. From an EHR4CR service provider's viewpoint, the business model simulation estimated that a profitability ratio of up to 1.8 could be achieved at year 1, with potential for growth in subsequent years depending on projected market uptake. CONCLUSIONS: By enhancing and speeding up existing processes, EHR4CR solutions promise to transform the clinical research landscape. The ecosystem defined provides the organisational framework for optimising the value and benefits for all stakeholders involved, in a sustainable manner. Our study suggests that the exploitation of EHR4CR solutions appears profitable and sustainable in Europe, with a growth potential depending on the rates of market and hospital adoption.