We evaluated the susceptibility to Ebola and Marburg virus infection of mice that cannot respond to interferon (IFN)-α/β and IFN-γ because of deletion of the STAT-1 gene. A mouse-adapted Zaire ebolavirus (ZEBOV) caused rapidly lethal disease; wild-type ZEBOV and Sudan Ebolavirus and 4 different Marburg virus strains produced severe, but more slowly progressive illness; and Reston Ebolavirus caused mild disease that was late in onset. The virulence of each agent was mirrored by the pace and severity of pathologic changes in the liver and lymphoid tissues. A virus-like particle vaccine elicited strong antibody responses but did not protect against mouse-adapted ZEBOV challenge.