Technical Abstract: Although the role of the parasitic mite, Varroa destructor, as a vector in transmission of viruses between honey bees is well established, no study has shown that it can similarly transmit Israeli Acute Paralysis Virus (IAPV), a virus that was found to be associated with Colony Collapse Disorder (CCD) in an initial survey. We demonstrate for the first time that Varroa mites are capable of transmitting IAPV in honey bees. The transmission experiments showed that when honey bees were exposed to Varroa mites that carried the virus, they could pick up infections, and that increased numbers of Varroa mites promoted the transmission of the virus. The transmission experiments also showed a route of mite-to-mite transmission in which virus-free mites became virus-positive by co-feeding on the same bees with virus-positive mites. The quantification of the virus showed that IAPV load in bees was positively correlated with the density of Varroa mites and that a prolonged period of Varroa feeding could lead to an increase in virus titer, suggesting that the Varroa mite is not only a vector but also an activator of IAPV in honey bees. Transcript levels of apidaecin and eater, proteins involved in honey bee immunity were shown to be up-regulated in response to Varroa mite infestation and IAPV infection. In addition, both replication of IAPV and the abundance of immune transcripts were affected by the different health backgrounds of bees. The observation of relatively lower levels of expression of immune transcripts and higher level of virus infection and titer in bees originating from weak colonies suggests that health conditions had a significant impact on the host immune-competence to resist virus infection. The information obtained from this study enhances our understanding of mechanisms of honey bee disease problems including CCD and could have important implications in the natural epidemiology of diseases.