Diagnostic errors are a relevant health-care problem. Although medical history taking is usually the first step in patients’ assessment there are only limited data on the association of its quality and diagnostic accuracy. Accordingly, this prospective randomized simulator-based single-blind trial aimed to investigate the effects of initial cues and history taking skills on diagnostic accuracy. 198 medical students (135 females) were given the task to assess a patient presenting with simulated acute pulmonary embolism. Participants were randomized to six versions of the scenario differing only in the initial cues, i.e., in the reply of the patient to the initial question about the reason for his visit. In three of six versions, initial cues were restricted to thoracic symptoms (chest pain, dyspnoea, or combination of both). In the remaining three versions, initial cues consisted of thoracic and extra-thoracic (leg pain, immobilization) symptoms. The primary outcome was diagnostic accuracy. The number of initial cues was unrelated to diagnostic accuracy. However, the combination of extra-thoracic and thoracic cues resulted in a higher diagnostic accuracy than thoracic cues only (52/96 vs. 35/102, p = 0.006). In multivariate regression, the number of questions asked from the categories “risk factors of pulmonary embolism” (regression coefficient 0.15, p < 0.001) and “dyspnea” (regression coefficient 0.12, p < 0.001) predicted diagnostic accuracy. Moreover, questions relating to “immobilization” (regression coefficient 0.42, p < 0.001), “onset of dyspnea” (regression coefficient 0.23, p = 0.003), and “modifying factors of chest pain” (regression coefficient 0.20, p = 0.04) independently predicted diagnostic accuracy. Interestingly, more systematic history taking was associated with lower diagnostic accuracy (regression coefficient −0.27, p < 0.001). The present trial demonstrates that during history taking cues initially revealed by the patient, kind and category of questions asked during the interview, and the interview’s structural systematics affect diagnostic accuracy.