The human high affinity receptor for IgE (FcεRI) is a cell surface structure critical for the pathology of allergic reactions. Human FcεRI is expressed as a tetramer (αβγ2) on basophils or mast cells and as trimeric (αβγ2) complex on antigen-presenting cells. Expression of the human a subunit can be down-regulated by a splice variant of FcεRIβ (βvar). We demonstrate that FcεRIα is the core subunit with which the other subunits assemble strictly cotranslationally. In addition to αβγ2 and αγ2, we demonstrate the presence of αβ and αβvarγ2 complexes that are stable in the detergent Brij 96. The role of individual FcεRI subunits for the formation of functional, immunoglobulin E-binding FcεRI complexes during endoplasmic reticulum (ER) assembly can be defined as follows: β and γ support ER insertion, signal peptide cleavage and proper N-glycosylation of α, whereas βvar allows accumulation of α protein backbone. We show that assembly of FcεRI in the ER is a key step for the regulation of surface expression of FcεRI. The ER quality control system thus regulates the quantity of functional FcεRI, which in turn controls onset and persistence of allergic reactions.