Smart Health is EU Strategic Value Chain that contributes to growth, jobs and competitiveness. Health Data is the main enabler for the value chain, but it also depends on cutting edge technologies - AI, cloud computing, IoT, to integrate the dispersed knowledge and support innovative healthcare solutions and services. EC sets the creation of a European Health Data Space as a main priority, to promote better exchange and access to health data. On a regional level, the RIS3 strategies of the involved widening countries - Bulgaria, Romania, Greece and Cyprus emphasize the need for based on Big Data, AI and IoT digitalized healthcare, to enable personalized medicine, informed decisions, and improved disease prediction. RIS3 strategies also outline the need for more funding for R&I, policy coherence and development of territorially join innovation strategies. A cross country coordinated approach is needed to align the separate endeavours towards an Excellent South-East Europe Smart Health Innovation Ecosystem enabled by a Regional Smart Health Data Space. VELES raises the level of innovation excellence in the South-East EU through creating a sustainable place-based innovation ecosystem, enabled by Regional Smart Health Data Space, including novel transformational framework, R&I and investment strategy and action plan for research, development and adoption of innovative and secure digital solutions that underpin the delivery of sustainable healthcare services. The Regional Smart Health Data Space will be demonstrated through the design of 4 interrelated pilots on Cancer treatment (Greece); Personalised/precision medicine of Alzheimer (Bulgaria); Cerebral tumours (Romania) and Dementia (Cyprus). The aim of VELES is to foster health data sharing regional and national strategies, to secure improved clinical practice, to preserve patient’s privacy and to empower citizens’ smart healthcare through access to innovative, cyber secure and data driven digital health services.