The chronic use of multiple medicinal drugs is growing, partly because individual patients’ drugs have not been adequately prescribed by primary care physicians. In order to reduce these polypharmacy problems, the Systematic Tool to Reduce Inappropriate Prescribing (STRIP) has been created. To facilitate physicians’ use of the STRIP method, the STRIP Assistant (STRIPA) has been developed. STRIPA is a stand-alone web-based decision support system that advices physicians during the pharmacotherapeutic analysis of patients’ health records. In this paper the application’s architecture and rule engine, and the design decisions relating to the user interface and semantic interoperability, are described. An experimental validation of the prototype by general practitioners and pharmacists showed that users perform significantly better when optimizing medication with STRIPA than without. This leads the authors to believe that one process-oriented decision support system, built around a context-aware rule engine, operated through an intuitive user interface, is able to contribute to improving drug prescription practices.