To overcome the inflammatory response in its host, the cattle-feeding, brown ear tick secretes histamine-binding proteins into the feeding site. These proteins are beta-barrels with two internal binding sites: a high-affinity (H) site for histamine and a site (L) for which the natural ligand is unknown. Here we report a related protein (SHBP), secreted by a rodent- and cattle-feeding tick, that traps both histamine and serotonin. The histamine-binding H site is well conserved in SHBP, whereas residue changes in the L-like site are consistent with binding of the bulkier serotonin molecule. As histamine is a key inflammatory mediator in cattle, while serotonin takes on this role in rodents, the diversification of these tick proteins may reflect host adaptation.