Eosinophils are important multifunctional granulocytes. When studying eosinophil function and its contribution to diseases, mouse models are often used. Mouse eosinophils selectively express sialic acidâbinding immunoglobulinâlike lectin (Siglec)âF. Its closest functional paralog on human eosinophils is Siglecâ8. These Siglecs are being used to target eosinophils when exploring their mechanistic roles in disease and for potential therapeutic benefit. In order to facilitate preclinical studies of human Siglecâ8, we developed transgenic mouse strains expressing human Siglecâ8 only on the surface of eosinophils with or without endogenous SiglecâF and have begun characterizing various cellular functions in vitro and in vivo. Eosinophils from Siglecâ8+ mice, with or without SiglecâF, responded to Siglecâ8 antibody engagement in vitro by upâregulating surface CD11b, whereas SiglecâF antibody had no such effect. Engagement of SiglecâF or Siglecâ8 with respective antibodies in vitro resulted in only modest increases in cell death. Administration of rat SiglecâF antibodies to mice led to a significant decrease in SiglecâF surface expression on eosinophils due to internalization, and thus appeared to decrease eosinophil numbers based on SiglecâF+ cells, but with proper gaiting strategies did not in fact result in significant eosinophil depletion. In marked contrast, administration of mouse Siglecâ8 antibodies rapidly and effectively depleted eosinophils from blood and spleens of mice, but an F(abâČ)2 version did not, indicating an Fcâmediated mechanism for eosinophil depletion in vivo. Siglecâ8 expressing mice with or without endogenous SiglecâF will be useful to study Siglecâ8âbased therapeutics, and may be a preferred approach when acute or chronic eosinophil depletion is needed.