Mouse and rat IgE and the respective soluble IgE-receptor complexes purified from rat basophilic leukemia cells were digested with trypsin. The end product in each case was F(ab')2-like. It contained the Ce2 regions, had intact antigen combining sites but had lost all ability to bind to the cell receptor for IgE. With mouse IgE the two principal sites of cleavage are likely to be the interdomain regions between Ce4:Ce3 and Ce3:C32 respectively. Cleavage at these sites occurs sequentially with the rate constant for the cleavage at the second site being approximately four-fold greater than that for the initial cleavage. When IgE is bound to the receptor the rates of cleavage are inhibited approximately three-fold. With rat IgE, the principal initial cleavage occurs within the intrachain disulfide loop in the Ce3 domain. Even when this disulfide bond in the digested protein is reduced, the product retains a substantial binding activity. A second cleavage occurs at a similar rate as the first and at a site analogous to that seen with mouse IgE, i.e. between the Ce3 and Ce2 domains. Notably, when bound to the receptor, the rate of cleavage at the first site is inhibited approximately three-fold but at the second site more than or equal to 40-fold. These results strongly implicate thd Ce3 domain as the principal site of interaction between rodent IgE and its receptor.