BackgroundGeneral practitioners play a unique key role in diagnosing patients with unclear diseases. Decision support systems in primary care can assist with diagnosis provided that they are efficient and user-friendly. ObjectivesThe objective of this study is to develop a high-fidelity prototype of the user interface of a clinical decision support system for primary care, particularly for diagnosis support in unclear diseases, using expert inspections at an early stage of development to ensure a high level of usability. MethodsThe user interface prototype was iteratively developed based on previous research, design principles, and usability guidelines. During the development phase, three usability inspections were carried out by all experts at four-week intervals as heuristic walkthrough. Each inspection consisted of two parts: 1) Task-based inspection 2) Free exploration and evaluation based on usability heuristics. Five domain experts assessed the current status of development.The tasks in the inspections were based on the task model derived in the requirements analysis: perform data entry, review and discuss results, schedule further diagnostics, refer to specialists and close case. ResultsAs a result of this iterative development, a high-fidelity, clickable user interface prototype was created that is able to fulfil all six tasks of our task model. The usability inspections identified a total of 196 usability issues (for all 3 inspections; Part 1: 90 issues, Part 2: 106 issues), ranging in severity from minor to severe. These served the continuous adjustment and improvement of the prototype. All main tasks were completed successfully despite these problems. ConclusionUsability inspections through heuristic walkthroughs can support and optimise the development of a user-centred decision support system in order to ensure its suitability for performing relevant tasks.