Considerable effort has gone into making mathematical and computer models of 
smallpox spread and control measures, typically consisting of vaccination and 
quarantine. The orally available antiorthopoxvirus drug tecovirimat has recently 
completed Phase 2 clinical trials and shows promise as a smallpox control agent. 
We constructed 2 computer simulations to explore the use of tecovirimat in 
combination with vaccination and social cooperativity to control an outbreak. 
Two scenarios were considered: (1) a homogenously mixed, deterministic 
simulation of a single metropolitan area; and (2) a stochastic network of the 50 
largest US metropolitan areas connected by commercial air traffic. 
Metropolitan-level mass vaccination coupled with drug treatment for all 
individuals who develop a fever considerably outperforms treating only those who 
develop smallpox's distinctive rash. Incorporating mass chemoprophylaxis 
represents another large improvement. More aggressive responses are more robust 
to low cooperation of the population with public health efforts and to faster 
disease spread. However, even with the most aggressive public health 
intervention, an attack that initially infects hundreds or thousands of 
individuals will need to be fought in multiple cities across the country.