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BACKGROUND This study aimed to evaluate whether the role-play (RP) of real patients by medical students as part of interactive clinical reasoning training can improve medical students' clinical performance. METHODS A total of 26 medical students volunteered to portray real patients within this program, and were defined as the RP group while the other 72 students were the non-RP group. In the interactive morning meeting, the medical students practiced how to approach the RP student as if they were encountering a real patient. All students were evaluated by mini-clinical evaluation exercises (mini-CEX) before and after this training program. RESULTS We found that all students had an increased total mini-CEX score after 4-weeks training, especially for interviewing skills. Notably, after training the RP students had significantly elevated total mini-CEX scores (51.23 ± 1.06 vs. 53.12 ± 1.11, p=0.028), and for counselling (7.15 ± 0.14 vs. 7.54 ± 0.18, p=0.015) and overall clinical competence (7.27 ± 0.15 vs. 7.65 ± 0.16, p=0.030). In contrast, the non-RP students had lower scores compared with those in the RP group, as revealed by both the pre- and post-training tests. Moreover, their mini-CEX scores were not improved after training. CONCLUSION Medical students who were motivated to RP real patients had better performance scores than those who did not. In addition, RP can enhance their counselling skills and clinical competences.