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 10 to 12 (46 students) participated in a participatory simulation of a virtual infectious disease as part of their science curriculum that took place in a university-laboratory school in Los Angeles, California. The results from our analyses revealed 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 and a missing curricular piece of computational viruses 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 implementing such online simulations to further students’ conceptual understanding.