Background Clinical practice guidelines are systematically developed statements intended to optimize patient care. However, a gapless implementation of guideline recommendations requires health care personnel not only to be aware of the recommendations and to support their content but also to recognize every situation in which they are applicable. To not miss situations in which recommendations should be applied, computerized clinical decision support can be provided through a system that allows an automated monitoring of adherence to clinical guideline recommendations in individual patients. Objective This study aims to collect and analyze the requirements for a system that allows the monitoring of adherence to evidence-based clinical guideline recommendations in individual patients and, based on these requirements, to design and implement a software prototype that integrates guideline recommendations with individual patient data, and to demonstrate the prototype’s utility in treatment recommendations. Methods We performed a work process analysis with experienced intensive care clinicians to develop a conceptual model of how to support guideline adherence monitoring in clinical routine and identified which steps in the model could be supported electronically. We then identified the core requirements of a software system to support recommendation adherence monitoring in a consensus-based requirements analysis within the loosely structured focus group work of key stakeholders (clinicians, guideline developers, health data engineers, and software developers). On the basis of these requirements, we designed and implemented a modular system architecture. To demonstrate its utility, we applied the prototype to monitor adherence to a COVID-19 treatment recommendation using clinical data from a large European university hospital. Results We designed a system that integrates guideline recommendations with real-time clinical data to evaluate individual guideline recommendation adherence and developed a functional prototype. The needs analysis with clinical staff resulted in a flowchart describing the work process of how adherence to recommendations should be monitored. Four core requirements were identified: the ability to decide whether a recommendation is applicable and implemented for a specific patient, the ability to integrate clinical data from different data formats and data structures, the ability to display raw patient data, and the use of a Fast Healthcare Interoperability Resources–based format for the representation of clinical practice guidelines to provide an interoperable, standards-based guideline recommendation exchange format. Conclusions Our system has advantages in terms of individual patient treatment and quality management in hospitals. However, further studies are needed to measure its impact on patient outcomes and evaluate its resource effectiveness in different clinical settings. We specified a modular software architecture that allows experts from different fields to work independently and focus on their area of expertise. We have released the source code of our system under an open-source license and invite for collaborative further development of the system.