Disease transmission is a fruitful domain in which to examine how scientific and folk theories interrelate, given laypeople’s access to multiple sources of information to explain events of personal significance. The current paper reports an in-depth survey of U.S. adults’ causal reasoning about two viral illnesses: a novel, deadly disease that has massively disrupted everyone’s lives, and a familiar, innocuous disease that has essentially no serious consequences. Participants received a series of closed-ended and open-ended questions probing their reasoning about disease (...) transmission, with a focus on causal mechanisms underlying disease contraction, transmission, treatment, and prevention; non-visible biological processes; and ontological frameworks regarding what kinds of entities viruses are. We also assessed participants’ attitudes, such as their trust in scientific experts and willingness to be vaccinated. Results indicated complexity in people’s reasoning, consistent with the co-existence of multiple explanatory frameworks. An understanding of viral transmission and viral replication existed alongside folk theories, placeholder beliefs, and lack of differentiation between viral and non-viral disease. For example, roughly 40% of participants who explained illness in terms of the transmission of viruses also endorsed a non-viral folk theory, such as exposure to cold weather or special foods as curative. Additionally, participants made use of competing modes of construal when explaining how viruses operate, such as framing the immune system response as cells trying to fight off the virus. Indeed, participants who displayed greater knowledge about viral transmission were significantly more likely to anthropomorphize bodily processes. Although comparisons of COVID-19 and the common cold revealed relatively few differences, the latter, more familiar disease elicited consistently lower levels of accuracy and greater reliance on folk theories. Moreover, for COVID-19 in particular, accuracy positively correlated with attitudes, self-protective behaviors, and willingness to be vaccinated. For both diseases, self-assessed knowledge about the disease negatively predicted accuracy. The results are discussed in relation to challenges for formal models of explanatory reasoning. (shrink)