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BACKGROUND: Simulated patient systems are vital in medical education and research, providing safe, integrative training environments and supporting clinical decision-making. Progressive Artificial Intelligence (AI) technologies, such as Large Language Models (LLM), could advance simulated patient systems by replicating medical conditions and patient-doctor interactions with high fidelity and low cost. However, effectiveness and trustworthiness remain challenging.METHODS: We developed AIPatient, a simulated patient system powered by LLM-based AI agents. The system incorporates the Retrieval Augmented Generation (RAG) framework, powered by six task-specific LLM-based AI agents for complex reasoning. For simulation reality, the system is also powered by the AIPatient KG (Knowledge Graph), built with de-identified real patient data from the Medical Information Mart for Intensive Care (MIMIC)-III database.RESULTS: Here we show that the system's accuracy in Electronic Health Record (EHR)-based medical Question Answering (QA), readability, robustness, and stability. Specifically, the system achieves a QA accuracy of 94.15% when all six agents, surpassing benchmarks with partial or no agent integration. Its knowledgebase demonstrates high validity (F1 score=0.89). Readability scores show median Flesch Reading Ease at 68.77 and median Flesch Kincaid Grade at 6.4, indicating accessibility to all medical professionals. Robustness and stability are confirmed with non-significant variance (ANOVA F-value = 0.6126, p > 0.1; F-value = 0.782, p > 0.1). A user study with medical students shows that AIPatient delivers high fidelity, usability, and educational value, matching or exceeding human-simulated patients in history-taking.CONCLUSIONS: Large language model-based simulated patient systems provide accurate, readable, and reliable medical encounters and demonstrates potential to transform medical education.