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To explore how students use and benefit from virtual patient cases (VPCs).In academic years 2013–2014 and 2014–2015, cohorts of students in pediatrics (Peds), family medicine (FM), and internal medicine (IM) clerkships were allocated to either core required use (CRU) or self-directed use (SU) of MedU VPCs. Outcomes included number and time of case review, student perception of learning from VPCs, National Board of Medical Examiners (NBME) subject examination scores, and summative clinical ratings for medical knowledge and differential diagnoses/problem solving. Focus groups were conducted each year. Mean differences were compared by t test.A total of 255 students participated in the study. Mean number of cases completed by the CRU group was significantly higher than that by the SU group (13.9 vs. 3.1 for FM, 16.1 vs. 3.9 for Peds, and 10.4 vs. 1.2 for IM) (P < .001). Student-perceived value ratings of VPCs were similar between groups. Students described VPCs as time consuming but useful for supplementing clinical conditions not seen in person. Mean scores on NBME subject examinations for CRU versus SU groups were not different between groups in any clerkship, nor were there significant differences in the summative clinical ratings for medical knowledge or differential diagnosis/clinical reasoning.Although VPCs continue to serve an important role in exposing students to clinical conditions not seen in person, the optimal employment of this technology in clerkship pedagogy requires further exploration.