Hospital readmissions within 30 days represent a burden for the patients and the entire health care system. Improving the care around hospital discharge period could decrease the risk of avoidable readmissions. We describe the methods of a trial that aims to evaluate the effect of a structured multimodal transitional care intervention targeted to higher-risk medical patients on 30-day unplanned readmissions and death. The TARGET-READ study is an investigator-initiated, pragmatic single-blinded randomized multicenter controlled trial with two parallel groups. We include all adult patients at risk of hospital readmission based on a simplified HOSPITAL score of ≥4 who are discharged home or nursing home after a hospital stay of one day or more in the department of medicine of the four participating hospitals. The patients randomized to the intervention group will receive a pre-discharge intervention by a study nurse with patient education, medication reconciliation, and follow-up appointment with their referring physician. They will receive short follow-up phone calls at 3 and 14 days after discharge to ensure medication adherence and follow-up by the ambulatory care physician. A blind study nurse will collect outcomes at 1 month by phone call interview. The control group will receive usual care. The TARGET-READ study aims to increase the knowledge about the efficacy of a bundled intervention aimed at reducing 30-day hospital readmission or death in higher-risk medical patients.