<p>We evaluated the effects of climatic factors, host and parasite species richness, and their phylogenetic and functional diversity on the nestedness and modularity of mammal-flea interaction networks from four biogeographic realms. We also tested for the associations between pure structural network dissimilarity (i.e., dissimilarity between host-sharing-by-fleas networks, <i>Dh</i>, or dissimilarity between flea-sharing-by-hosts networks, <i>Df</i>) and environmental dissimilarity, and host and flea compositional, phylogenetic, and functional dissimilarities. We asked whether (a) the relative effects of these factors differ between biogeographic realms and (b) the network structure is more strongly driven by environmental, geographic, host-associated, or flea-associated factors. The climatic drivers of nestedness and modularity differed between realms. The networks in different realms responded to different factors, with the directions of some of these effects being opposite. Among interactor-associated factors, host species richness was most often detected as an important driver of nestedness, whereas flea species richness mainly affected modularity. <i>Dh</i> was mostly explained by host-associated and, to a lesser extent, flea-associated dissimilarity. No effect of host-associated dissimilarity on <i>Df</i> was detected, but it was linked with flea-associated dissimilarity in two of the four realms. Environmental dissimilarity weakly affected <i>Dh</i> and did not affect <i>Df.</i> We conclude that between-realm differences in the drivers of network structure resulted from an interplay of ecological and historical factors, whereas between-interactor differences in their effects on the network structure arose due to the asymmetry in host-flea relationships.</p>