Both enhancements and impairments of clinical performance due to acute stress have been reported, often as a function of the intensity of an individual's response. According to the broader stress literature, peripheral or extrinsic stressors (ES) and task-contingent or intrinsic stressors (IS) can be distinguished within a stressful situation. The objective of this study was to assess the impact of IS and ES on clinical performance. A prospective randomized crossover study was undertaken with third-year medical students conducting two medical experiences with simulated patients. The effects of severity of the disease (IS) and the patient's aggressiveness (ES) were studied. A total of 109 students were assigned to four groups according to the presence of ES and IS. Subjective stress and anxiety responses were assessed before and after each experience. The students' clinical skills, diagnostic accuracy and argumentation were assessed as clinical performance measures. Sex and student-perceived cognitive difficulty of the task were considered as adjustment variables. Both types of stressors improved clinical performance. IS improved diagnostic accuracy (regression parameter β = 9.7, p = 0.004) and differential argumentation (β = 5.9, p = 0.02), whereas ES improved clinical examination (β = 12.3, p < 0.001) and communication skills (β = 15.4, p < 0.001). The student-perceived cognitive difficulty of the task was a strong deleterious factor on both stress and performance. In simulated consultation, extrinsic and intrinsic stressors both have a positive but different effect on clinical performance.