Membrane-bound IgE (mIgE) is part of the IgE–BCR and is essential for generating isotype-specific IgE responses. On mIgE+ B cells, the membrane-bound ε-chain (mε) exists predominantly in the long isoform, mε L, containing an extra 52 aa CεmX domain between CH4 and the C-terminal membrane-anchoring segment; the short isoform of mε, mε S, exists in minor proportions. CεmX thus provides an attractive site for immunologic targeting of mIgE+ B cells. In this study, we show that nine newly prepared CεmX-specific mAbs, as well as the previously reported a20, bound to mIgE. Fc L-expressing CHO cells, while only 4B12 and 26H2 bound to mIgE. Fc L-expressing B cell line Ramos cells. The mAb 4B12 bound to the N-terminal part, 26H2 the middle part, and all others the C-terminal part of CεmX. Expression of Igα and Igβ on the mIgE. Fc L-CHO cells reduces the binding of a20 to CεmX as compared with that of 4B12 and 26H2. The chimeric mAbs c4B12 and c26H2, when cross-linked by secondary antibodies, lysed mIgE. Fc L-Ramos cells by apoptosis through a BCR-dependent caspase pathway. Using PBMCs as the source of effector cells, c4B12 and c26H2 demonstrated Ab-dependent cellular cytotoxicity toward mIgE. Fc L-Ramos cells in a dose-dependent fashion. In cultures of PBMCs from atopic dermatitis patients, c4B12 and c26H2 inhibited the synthesis of IgE driven by anti-CD40 and IL-4. These results suggest that 4B12 and 26H2 and an immunogen using the peptide segments recognized by these mAbs are potentially useful for targeting mIgE+ B cells to control IgE production.