This study aimed to investigate whether group self-practice of systematic clinical observation using the airway, breathing, circulation, disability and exposure (ABCDE) approach in a multiplayer, immersive, interactive virtual reality (VR) application provided a non-inferior learning outcome compared to practicing with physical equipment in first-year medical and nursing students. The study was a non-inferior, parallel-group randomized controlled trial. After a 15-min introduction session on the ABCDE approach, all students were randomly allocated to practice ABCDE in groups of three for 20 min either in a fully immersive, interactive, multiplayer virtual reality application (the VR group) or with physical equipment (the TP group). The primary outcome was the number of students who documented all predefined observations in the correct order of the ABCDE approach on a practical test performed immediately after group practice. A total of 84% of all eligible students participated, with 146 students in the VR group and 143 in the TP group. On the primary outcome, 20% in the VR group and 21% in the TP group got everything correct (absolute difference 1% point, one-sided 95% confidence interval 1.0-8.8% points), showing non-inferiority of the virtual reality application. For other outcomes, the results were mostly similar between the groups. Group self-practice of the ABCDE approach in multiplayer, immersive, interactive virtual reality application was non-inferior to practice with physical equipment.