Abstract Background In the time of the coronavirus disease 2019 (COVID-19) pandemic, in-person lectures had to be shifted to online learning. This study aimed to evaluate students’ and lecturers’ perception and effectiveness of a virtual inverted classroom (VIC) concept on clinical radiology in comparison to a historic control. Methods In the winter semester 2020/21, 136 fourth year medical students who completed the clinical radiology VIC during the pandemic, were included in the single centre, prospective study. Results were compared with a historic control that had finished the physical inverted classroom (PIC) in the immediately preceding year. The VIC consisted of an initial phase of self-determined preparation with learning videos and a second interactive phase of clinical case studies alternating between the virtual lecture hall and virtual buzz groups. At the end of the lecture series, students rated the lecture on a scale of 1 (most positive assessment) to 6 (most negative assessment) through an online survey platform. Additionally, they reported their impressions in free-form text. Lecturers were invited to comment on the VIC in a group interview. Main outcomes were final grades and student perception of the VIC. Results Students’ general impression of VIC was lower than that of PIC (median value of 3 [IQR 4, 2] and 1 [IQR 0, 0], p < 0.001), respectively, p < 0.001). The highest rating was achieved concerning use of the audience response system (median 1 [IQR 1, 0]), and the lowest concerning the buzz groups (median 4 [IQR 5, 3]). Students stated that they would have appreciated more details on reading images, greater focus on plenary case studies, and provision of exam related scripts. Lecturers would have liked better preparation by students, more activity of students, and stronger assistance for group support. Exam grades after VIC were better than after PIC (median 1 [IQR 2, 1] and 2 [IQR 2,1], respectively, p < 0.001). Conclusions Students’ overall perception of VIC was satisfactory, although worse than PIC. Final grades improved compared to PIC. Provided an adapted buzz group size and support, VIC may serve as complement in medical education once the pandemic is over.