This study investigated students’ understanding of a virtual infectious disease in relation to their understanding of natural infectious diseases. Two sixth-grade classrooms of students between the ages of 10 and 12 (46 students) took part in a participatory simulation of a virtual infectious disease, which was integrated into their science curriculum. The results from our analyses reveal that students perceived the simulation as similar to a natural infectious disease and that the immersive components of the simulation afforded students the opportunity to discuss their understandings of natural disease and to compare them to their experiences with the virtual disease. We found that while the virtual disease capitalized on students’ knowledge of natural infectious disease through virtual symptoms, these symptoms may have led students to think of its transfer more as an observable or mechanical event rather than as a biological process. These findings provide helpful indicators to science educators and educational designers interested in creating and integrating online simulations within classroom environments to further students’ conceptual understanding.