BACKGROUND Managing patients with polypharmacy is a challenging issue in primary care. The aim of this study is to determine whether a patient-centered systematic review leads to more appropriate medication use in patients without negatively affecting quality of life and the course of the disease. METHODS/DESIGN The trial is a two-armed, double blinded cluster-randomized controlled trial. Primary care physicians (PCPs) will be randomly assigned to the intervention or control group. Physicians in the intervention group undergo training with instruction of the algorithm. The control group is given a lecture on multimorbidity and instructions for collecting data in a usual care manner. PCPs will approach patients aged 60 years or older who are taking 5 or more drugs. The study period is 1 year. The primary outcome measure is the change in the number of drugs 12 months after the algorithm was applied by the PCP during consultation with the patient. Secondary outcomes are: change in the number of drugs immediately after the encounter and 6 months later, reason for a change of the medication, discrepancy in the decision to change between PCP and patient, number of drugs for which the patient is suggesting a change, number of drugs the patient is taking that are not known to the PCP, time consumption of the intervention, disease-specific variables to evaluate the course of the disease(s) for which the patient is being treated , quality of life, barriers against using the algorithm, numbers of drugs readopted due to an unfavorable course of the disease, and numbers of drugs which have been started. DISCUSSION Answering the four questions of the algorithm requires a weighing-up of risks and benefits and contains a shared-decision-making approach: a prioritization of the treatment goals is necessary. This can only be done in collaboration with the patient. The majority of patients with multimorbidity are treated in the primary care setting. This underlines the significance of our study carried out in this setting: given the high prevalence of adverse drug events in patients with multimorbidity an intervention like ours has a large potential to reduce drug-related morbidity. TRIAL REGISTRATION ISRCTN16560559 13 November 2014.