Technical Abstract: Newcastle Disease Virus (NDV) is an avian paramyxovirus that has caused significant economic losses to the US poultry industry. Despite the fact that a live-attenuated vaccine has been used for decades, outbreaks of highly virulent strains still occur periodically. To create rationally-designed recombinant vaccines, a more thorough understanding of the host response to infection is required. There is limited knowledge about the avian response to paramyxoviruses, and how this response may contribute to disease. In this study, the early host response to a recent NDV outbreak strain of high virulence is characterized in vivo using microarray. A strong host response is observed with groups of genes involved in innate anti-viral and pro-inflammatory responses being significantly induced. Among these are numerous interferons, cytokines, chemokines, interferon effectors and inducible nitric oxide synthase, and high levels of nitric oxide were detected in serum of infected birds at days 2 and 3 post-inoculation. In vitro experiments showed induction of key host response genes, interferons alpha and beta and interleukins 1beta and 6, in splenic lymphocytes at 6 hours post-infection, as well. The robust host response to NDV shown here, and the rapid mortality of this outbreak strain, provide evidence that the host response itself may significantly contribute to disease.