Several genome-wide yeast-two-hybrid (Y2H) studies of proteinprotein interactions in eukaryotes have been published over the last years, including Saccharomyces cerevisiae [11] , Caenorhabditis elegans [12] , Drosophila melanogaster [13] , Plasmodium falciparum [14] and Homo sapiens [15, 16] . The first complete genome-wide interaction study, however, was published for the E.coli phage T7 [17] . With their relatively small genomes and few genes, viruses seem the ideal candidates for studying protein-protein interactions on a genome-wide level and to address the generally low coverage of Y2H measurements in a systematic way. It is therefore surprising that not more genome-wide studies of intraviral interactions have been performed to date. With the exception of bacteriophage T7 [17] and Vaccinia virus [18] , most of the studies of viral interactions have been performed on small RNA viruses [19, 20, 21, 22] . Recently more studies have been focusing on larger DNA viruses. In addition to our previous studies of VZV and Kaposi's sarcoma-associated herpesvirus (KSHV) [23] , a study by Calderwood and colleagues identified 43 interactions between viral proteins in Epstein-Barr virus (EBV) [24] . Two Y2H studies on herpes simplex virus 1 (HSV-1) and KSHV have also focused on interactions between structural components of these viruses [25, 26] . To add to our understanding of intraviral interactions in herpesviruses we present in this article the first interactomes for herpes simplex virus I and murine cytomegalovirus (mCMV), in addition to a second and independent interactome for Epstein-Barr virus. Based on these data we are able to compare five related interactomes, obtained using a standardized experimental setup for all five species. From the comparison and extensive experimental testing by CoIP we conclude that i) genome-wide interaction studies are sufficiently sensitive for between-species comparisons to identify the basic sunflower structure of the interaction networks and their common core, ii) interactions are to a large degree conserved between orthologs in herpesviruses, iii) comparing interactomes from several species can improve the low coverage of individual Y2H measurements and iv) biologically relevant interactions which may not be apparent from the interactome of a single species, often become obvious when multiple interactomes are aligned and compared.