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Several alternatives to formalin-stored physical specimens have been described in medical literature, but only a few studies have addressed the issue of learning outcomes when these materials were employed. The aim of this study was to conduct a prospective controlled study to assess student performance in learning anatomic pathology when adding three-dimensional (3D) virtual models as adjunct teaching materials in the study of macroscopic lesions. Third-year medical students (n = 501) enrolled at the Victor Babes University of Medicine and Pharmacy in Timisoara, Romania, were recruited to participate. Student performance was assessed through questionnaires. Students performed worse with new method, with poorer results in terms of overall (mean 77.6% ±SD 11.8% vs. 83.6% ±10.5) and individual question scores (percentage of questions with maximum score 34.6% ±25.6 vs. 47.7 ± 24.6). This decreased performance was generalizable, as it was observed across all language divisions and was independent of the teaching assistant involved in the process. In an open-ended feedback evaluation of the new 3D specimens, most students agreed that the new method was better, bringing arguments both for and against these models. Although subjectively the students found the novel teaching materials to be more helpful, their learning performance decreased. A wider implementation as well as exposure to the technique and use of virtual specimens in medical teaching could improve the students' performance outcome by accommodating the needs for novel teaching materials for digital natives.