Even though more immunoglobulin A (IgA) is produced in humans than all other isotypes combined, relatively little is known about receptors that bind the Fc part of IgA. The myeloid IgA receptor, FcRI (CD89), triggers various effector functions in vitro, but its in vivo role remains unclear. Here, a transgenic mouse model is described in which FcRI is expressed under its own regulatory sequences. Receptor expression and regulation by cytokines was comparable to the human situation and hFcRI can trigger phagocytosis and lysis of tumor cells. To analyze the contribution of the FcR γ chain or the β2 integrin CR3 (CD11b/CD18) in FcRI biological function, FcRI transgenic mice were crossed with either FcR γ chain −/− or CR3 −/− mice. In contrast to in vitro data, FcR γ chain was essential for surface expression of hFcRI in vivo. Functional studies in hFcRI/ γ−/−mice were, therefore, limited. In vitro studies showed FcR γ chain to be necessary for phagocytosis. Neither hFcRI expression nor phagocytosis, triggered via hFcRI, were influenced by CR3. Remarkably, the capacity to lyse tumor targets was ablated in hFcRI transgenic/ CR3−/− mice, although binding of neutrophils to tumor cells was intact. This shows a previously unrecognized importance of CR3 for hFcRI-mediated antibody-dependent cellular cytotoxicity (ADCC).