Backgrounds <p>Traditional methods of teaching history-taking in medical education are limited by scalability and resource intensity. This study aims to assess the effectiveness of simulated patient interactions based on a custom-designed Generative Pre-trained Transformer (GPT) model, developed using OpenAI’s ChatGPT GPTs platform, in enhancing medical students’ history-taking skills compared to traditional role-playing methods.</p> Methods <p>A total of 56 medical students were randomly assigned into two groups: an GPT group using GPT-simulated patients and a control group using traditional role-playing. Pre- and post-training assessments were conducted using a structured clinical examination to measure students’ abilities in history collection, clinical reasoning, communication skills, and professional behavior. Additionally, students’ evaluations of the educational effectiveness, satisfaction, and recommendation likelihood were assessed.</p> Results <p>The GPT-simulation group showed significantly higher post-training scores in the structured clinical examination compared to the control group (86.79 ± 5.46,73.64 ± 4.76, respectively, <i>P</i> &lt; 0.001). Students in the GPT group exhibited higher enthusiasm for learning, greater self-directed learning motivation, and better communication feedback abilities compared to the control group (<i>P</i> &lt; 0.05). Additionally, the student satisfaction survey revealed that the GPT group rated higher on the diversity of diseases encountered, ease of use, and likelihood of recommending the training compared to the control group (<i>P</i> &lt; 0.05).</p> Conclusions <p>GPT-based history-taking training effectively enhances medical students’ history-taking skills, providing a solid foundation for the application of artificial intelligence (AI) in medical education.</p> Clinical trial number <p>NCT06766383.</p>