Ebola virus causes a severe hemorrhagic fever syndrome in man with high case-fatality rates. Following infection, monocytes and macrophages are among the first cells targeted by the virus. These cells respond by increasing expression of inflammatory cytokines and chemokines that contribute towards pathogenesis. In order to more thoroughly characterize the host response to Ebola infection, primary human macrophages were infected with Zaire ebolavirus and samples harvested for transcriptional changes after 1 or 6 hours post infection. Whereas previous studies have analyzed a relatively small subset of host genes, this study examined the transcriptional profile of over 10,000 genes and employed rigorous pathway analyses to the datasets. Ebola virus was found to significantly regulate the expression of over 88 host genes. These changes occurred within the first hours of infection. Subsequent experiments demonstrated that virus replication was not necessary for activation. Indeed, noninfectious virus-like particles expressing the ebolavirus glycoprotein and matrix proteins were sufficient stimuli to induce activation. 