The influence of predator-prey systems and interactions on wildlife passage use by mammals has received little attention to date. Predator-prey systems vary throughout the world and across regions. Europe and North America are characterised largely by predator-prey systems in which predator and prey have co-evolved. However, large predators are absent from many areas, enabling prey species (e.g., ungulates) to range in predator-free environments. In mainland Australia, the main predator species are evolutionary novel and have not co-evolved with native prey. These fundamental differences in predator-prey systems potentially influence species’ behavior and, it is argued, species’ response to passage environments. Predator-prey systems also operate at different spatial scales. The spatial distribution of large mammals is influenced by regional scale predator-prey interactions that potentially influence the species encountering passages. Medium-sized and small mammals tend to operate at more refined geographical scales and passage avoidance or acceptance may be more influenced by localised predator-prey interactions and in response to the passage structure. Biotic interactions at passage approaches and within passage confines potentially influence the successful transit of the passage. This paper examines the documented and potential influence of predator-prey interactions on wildlife passage use by mammals, and passage effects on predator and prey interactions. It considers predator-prey relationships relative to various spatial scales and takes into account biotic interactions that may occur at passage sites. The potential influences of relaxed selection and co-evolution of predator and prey on predator-prey systems and mammalian responses to passage environments are particularly addressed. It is concluded that extrapolation of management recommendations resulting from passage studies under different predator-prey systems need to be treated cautiously. The influence of predator-prey interactions on passage response by mammalian fauna appears to have been underestimated in passage studies to date and warrants further scientific investigation.