Background Preventive strategies to reduce clinically significant medication errors (MEs), such as medication review, are often limited by human resources. Identifying high-risk patients to allow for appropriate resource allocation is of the utmost importance. To this end, we developed a predictive model to identify high-risk patients and assessed its impact on clinical decisionmaking. Methods From March 1st to April 31st 2014, we conducted a prospective cohort study on adult inpatients of a 1,644-bed University Hospital Centre. After a clinical evaluation of identified MEs, we fitted and internally validated a multivariate logistic model predicting their occurrence. Through 5,000 simulated randomized controlled trials, we compared two clinical decision pathways for intervention: one supported by our model and one based on the criterion of age. Results Among 1,408 patients, 365 (25.9%) experienced at least one clinically significant ME. Eleven variables were identified using multivariable logistic regression and used to build a predictive model which demonstrated fair performance (c-statistic: 0.72). Major predictors were age and number of prescribed drugs. When compared with a decision to treat based on the criterion of age, our model enhanced the interception of potential adverse drug events by 17.5%, with a number needed to treat of 6 patients. Conclusion We developed and tested a model predicting the occurrence of clinically significant MEs. Preliminary results suggest that its implementation into clinical practice could be used to focus interventions on high-risk patients. This must be confirmed on an independent set of patients and evaluated through a real clinical impact study.