The threat of bioterrorism and the possibility of accidental release have spawned a growth of interest in modeling the course of the release of a highly pathogenic agent. Studies focused on strategies to contain local outbreaks after their detection show that timely interventions with vaccination and contact tracing are able to halt transmission. However, such studies do not consider the effects of human mobility patterns. Using a large-scale structured metapopulation model to simulate the global spread of smallpox after an intentional release event, we show that index cases and potential outbreaks can occur in different continents even before the detection of the pathogen release. These results have two major implications: i) intentional release of a highly pathogenic agent within a country will have global effects; ii) the release event may trigger outbreaks in countries lacking the health infrastructure necessary for effective containment. The presented study provides data with potential uses in defining contingency plans at the National and International level.