Computer-based clinical practice guidelines often need to be modified when medical knowledge evolves or when guidelines are implemented in a local setting with specific constraints and preferences. To enable easy modifications to guidelines and maintain their integrity, we have developed a methodology for modular representation of guidelines. Using this approach, we create guidelines in a hierarchical and modular manner. We use the Axiomatic Design methodology to facilitate the development of independent modules. Design matrices capture the interactions among modules. The design matrices can be used during guideline modification to create a change process and to enable identification of other modules that are affected by a change to a module. We implemented this modular knowledge representation approach by incorporating it into the Guideline Interchange Format (GLIF) language. We applied this approach to encode parts of three outdated guidelines released during 2000-2001, and we revised these designs to model updated releases of the guideline. Qualitative and quantitative metrics were developed to assess the types of changes made to the encoded guidelines.