Patients are often required to follow a medical treatment after discharge, e.g., for a chronic condition, rehabilitation after surgery, or for cancer survivor therapies. The need to adapt to new lifestyles, medication, and treatment routines, can produce an individual burden to the patient, who is often at home without the full support of healthcare professionals. Although technological solutions-in the form of mobile apps and wearables-have been proposed to mitigate these issues, it is essential to consider individual characteristics, preferences, and the context of a patient in order to offer personalized and effective support. The specific events and circumstances linked to an individual profile can be abstracted as a patient trajectory, which can contribute to a better understanding of the patient, her needs, and the most appropriate personalized support. Although patient trajectories have been studied for different illnesses and conditions, it remains challenging to effectively use them as the basis for data analytics methodologies in decentralized eHealth systems. In this work, we present a novel approach based on the multi-agent paradigm, considering patient trajectories as the cornerstone of a methodology for modelling eHealth support systems. In this design, semantic representations of individual treatment pathways are used in order to exchange patient-relevant information, potentially fed to AI systems for prediction and classification tasks. This paper describes the major challenges in this scope, as well as the design principles of the proposed agent-based architecture, including an example of its use through a case scenario for cancer survivors support. Keywords Patient trajectories • Semantic modeling • Agent-based modeling This article is part of the Topical Collection on Healthcare Intelligent Multi-Agent Systems (HIMAS2020)