Technical Abstract: Many vertebrate and insect viruses posses anti-apoptotic genes that are required for their infectivity. This has led to the hypothesis that apoptosis is an innate immunoresponse important for limiting virus infections. The role of apoptosis may be especially important in insect anti-viral defense because of the lack of adaptive immunity. However, the cellular mechanism that elicits apoptosis in response to viral infection in insects has not been determined. Moreover, observations from cultured cells seem to suggest that apoptosis is a late response to viral proliferation and thus has little role in limiting infection. Using an in vivo infection system with the mosquito Baculovirus CuniNPV, we demonstrated that mx, the mosquito ortholog of Drosophila pro-apoptotic gene reaper, is specifically induced in larval midgut cells following viral infection. More importantly, rapid induction of mx and apoptosis plays a significant role in determining the susceptibility to CuniNPV infection in a non- permissive host. Inhibition of apoptosis with caspase inhibitor allowed infection of CuniNPV to become established in larvae of an otherwise refractory mosquito Aedes aegypti . Our study provides the first evidence that a reaper-like pro-apoptotic gene is involved in mediating insect innate immunity. In addition, it demonstrated that pro-apoptotic response could play a significant role in limiting viral infection and determining vector compatibility.