Background Due to an increase in life expectancy, the prevalence of chronic diseases is also on the rise. Clinical practice guidelines (CPGs) provide recommendations for suitable interventions regarding different chronic diseases, but a deficiency in the implementation of these CPGs has been identified. The PITeS-TiiSS (Telemedicine and eHealth Innovation Platform: Information Communications Technology for Research and Information Challenges in Health Services) tool, a personalized ontology-based clinical decision support system (CDSS), aims to reduce variability, prevent errors, and consider interactions between different CPG recommendations, among other benefits. Objective The aim of this study is to design, develop, and validate an ontology-based CDSS that provides personalized recommendations related to drug prescription. The target population is older adult patients with chronic diseases and polypharmacy, and the goal is to reduce complications related to these types of conditions while offering integrated care. Methods A study scenario about atrial fibrillation and treatment with anticoagulants was selected to validate the tool. After this, a series of knowledge sources were identified, including CPGs, PROFUND index, LESS/CHRON criteria, and STOPP/START criteria, to extract the information. Modeling was carried out using an ontology, and mapping was done with Health Level 7 Fast Healthcare Interoperability Resources (HL7 FHIR) and Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT; International Health Terminology Standards Development Organisation). Once the CDSS was developed, validation was carried out by using a retrospective case study. Results This project was funded in January 2015 and approved by the Virgen del Rocio University Hospital ethics committee on November 24, 2015. Two different tasks were carried out to test the functioning of the tool. First, retrospective data from a real patient who met the inclusion criteria were used. Second, the analysis of an adoption model was performed through the study of the requirements and characteristics that a CDSS must meet in order to be well accepted and used by health professionals. The results are favorable and allow the proposed research to continue to the next phase. Conclusions An ontology-based CDSS was successfully designed, developed, and validated. However, in future work, validation in a real environment should be performed to ensure the tool is usable and reliable.