<p>Ensuring the safety of Artificial Intelligence-enabled Computer-Aided Diagnosis systems is critical because diagnostic errors can have serious consequences for patient care. However, existing regulatory and risk management frameworks often do not sufficiently address the complex socio-technical interactions between clinicians and Artificial Intelligent systems, leaving key human-centered safety challenges underexplored. This paper presents a systematic and human-centered approach to deriving safety design guidelines for clinician-Artificial Intelligence interaction in Computer-Aided Diagnosis systems using System-Theoretic Process Analysis. Through this analysis, we identify critical hazards associated with clinician–Artificial Intelligence collaboration, including automation bias on system recommendations, and misinterpretation of explanations. Based on the identified unsafe control actions, we formulate a set of actionable and traceable safety design guidelines that promote transparency, coherent explanations, and calibrated trust in Artificial Intelligence-assisted decision-making. To bridge safety analysis and system design, the proposed guidelines are operationalized within a Computer-Aided Diagnosis interaction framework. The framework includes a safety-oriented Graphical User Interface that integrates multiple explanation methods and interactive mechanisms to promote clinician engagement. Furthermore, we introduce a safety-oriented evaluation approach that uses consistency across multiple explanation methods as a quantitative indicator of potentially unreliable or ambiguous explanations. By linking System-Theoretic Process Analysis, interaction design, and explainability evaluation, this work provides a unified and reusable framework for improving the safety and reliability of Artificial Intelligence-driven Computer-Aided Diagnosis systems.</p>