Personalization of eHealth systems is a promising technique for improving patients’ adherence. This paper explores the possibility of personalisation based on the patients’ medical health situation and on their health literacy. The study is set within the context of a self-management support system (SMSS) for renal transplant patients. A SMSS is designed with layering, nudging, emphaticizing, and focusing principles. It has two communication styles: (1) a guided style that provided more interpretation support and addressed emotional needs; and (2) a factual style that showed only measurement history, medical information, and recommendations. To evaluate the design, 49 renal transplant patients with three different experience levels participated in a lab study, in which they used the system in imaginary scenarios to deal with three medical health situations (alright, mild concern, and concern). A 96% understanding and 87% adherence rate was observed, with a significant interaction effect on adherence between patient group and health situation. Furthermore, compared to recently transplanted patients, not recently transplanted patients were relatively more positive towards the factual than the guided communication style in the “alright” condition. Furthermore, additional medical information was searched more often in health situations that causes mild concern and a majority of patients did not change the communication style to their preferred styles. By attuning the communication style to patient’s experience and medical health situation according to the applied principles and acquired insights, SMSSs are expected to be better used.