Objectives: to design an EHR-agnostic, CDSS for personalized medicine approaches in the management of Parkinson's disease (PD) that complements symptomatic treatment by adopting a holistic strategy, as well as passive (with IoT devices) and active (with diaries) patient monitoring. Methods: the design is based on the recent literature on CDSS, the findings of previous studies evaluating mhealth for the management of Parkinson’s and the analysis of user needs that defined shared decision making, flexibility that accounts for variation among clinicians and monitoring of information integration from multiple sources as the main design principles. Results: PRIME is a traditional CDSS in the sense that it is comprised of interoperable, FHIR compliant, software designed to be a direct aid to clinical-decision making; the characteristics of an individual patient derived from EHRs, IoT devices such as Apple iWatch and diary data, and processed with machine learning methods, are matched to a computerized clinical knowledge base (derived from Clinical Guidelines, drug and gene interaction DBs and the PD ontology) and patient-specific assessments or recommendations are then presented to the clinician for a decision through a dedicated, user interface. Conclusions: PRIME which is co‐financed by the European Regional Development Fund of the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH – CREATE – INNOVATE (project code:Τ2EDK- 05199) will be an evidenced-based CDSS capable of leveraging data and observations otherwise unobtainable or uninterpretable by humans and produce appropriate alerts.