Background: Virtual patients (VPs) are narrative-based educational activities to train clinical reasoning in a safe environment. Our aim was to explore the influence of the design of the narrative and level of difficulty on the clinical reasoning process, diagnostic accuracy and time-on-task. Methods: In a randomized controlled trial, we analyzed the clinical reasoning process of 46 medical students with six VPs in three different variations: (1) patients showing a friendly behavior, (2) patients showing a disruptive behavior and (3) a version without a patient story. Results: For easy VPs, we did not see a significant difference in diagnostic accuracy. For difficult VPs, the diagnostic accuracy was significantly higher for participants who worked on the friendly VPs compared to the other two groups. Independent from VP difficulty, participants identified significantly more problems and tests for disruptive than for friendly VPs; time on task was comparable for these two groups. The extrinsic motivation of participants working on the VPs without a patient story was significantly lower than for the students working on the friendly VPs. Conclusions: Our results indicate that the measured VP difficulty has a higher influence on the clinical reasoning process and diagnostic accuracy than the variations in the narratives.