Technical Abstract: Controlling the transmission of microorganisms by hematophagous arthropods represents one of the main challenges to human and animal health worldwide. Recently, a great deal of interest has been focused on the possibility of developing vaccines directed to the vectors of these diseases. The saliva of hematophagous arthropods is one of the targets of this anti-vector vaccine approach because of the crucial role it plays in the transmission cycle of arthropod-borne diseases. In a remarkable example of convergent evolution the saliva of all hematophagous arthropods contain a species-specific cocktail of anti-hemostatic molecules. As a result, vaccines directed to these salivary proteins tend to be species-specific. However, given the conservation of arthropod glycans through evolution, it is theoretically possible to induce pan-arthropod immunity targeting the N-linked and O-linked glycans that are attached to salivary proteins during their transit through the Golgi system before secretion. In order to study this possibility we immunized mice with glycoproteins derived from the non-hematophagous arthropod Drosophila melanogaster and characterized the reactivity of the induced antibodies to antigens from eight different species of hematophagous arthropods: the sand flies Lutzomyia longipalpis and Phlebotomus papatasi, the biting midge Culicoides sonorensis, the mosquitoes Aedes triseriatus, Aedes aegypti, Anopheles gambiae and Culex pipiens and the hard tick Ixodes scapularis. A subset of D. melanogaster proteins which are solubilized at high temperatures (thermosoluble proteins) was found to induce cross-reactive antibodies that recognize several tissues, including salivary glands and midguts, of hematophagous arthropods. Three of the main D. melanogaster thermosoluble proteins (drosocrystallin, TSol-52 and TSol-30) were identified by mass spectrometry and their sequence compared to that of salivary proteins of A. aegypti and A. triseriatus female mosquitoes recognized by these cross-reactive antibodies. We conclude that arthropod glycans are not responsible for this cross-reactive immunity and propose an alternative structure as responsible for this cross-reactive immunity, low complexity domains present in Drosophila and Aedes salivary proteins.