The presence of comorbidities and multiple chronic diseases, and the related prescription of complex medications, as well as concerns in therapies changes, present many professional challenges in the clinical decision-making process. Multiple medications’ use (i.e. polypharmacy), is common in this population, and could be associated to adverse outcomes and presence of drug-drug interactions. The present study aims at investigating the variables impacting on the clinical choice, and the potential support of digital innovation and other knowledge asset, such as IntercheckWEB and/or guidelines, to optimize the prescription decision making process in older and frailer patients, in polytherapy. A review on the topic is performed for revealing the principal social and clinical factors, impacting on the clinicians’ propensity to chance the patients’ therapy. An observational study was conducted, involving head physicians and clinicians (N=35) referring to the Internal Medicine wards, of five Italian medium size hospitals. In June 2019, each clinician completed a questionnaire, aimed at evaluating 15 clinical cases, thus defining if in case of specific information derived from IT systems (such as INTERCheckWEB), they would have changed the patient’s current therapy, during an Internal Medicine hospitalization. Data were analysed considering three methodological approaches. i) Relationships between variables, were investigated to test the existence of correlations among them. ii) A hierarchical sequential linear regression model was implemented to define the predictors of the clinician propensity to change therapy. iii) A Qualitative Comparative Analysis – QCA, was implemented, in order to complement previous statistical approaches, with a comparative-configurational one. Results reported that patient’s age (β = 0.505