We have investigated the ability of an antisense immunoglobulin E (IgE) receptor α-subunit oligodeoxynucleotide (FcεRIα ODN) specifically to inhibit IgE-mediated allergic reactions in the mouse. Synthetic antisense FcεRIα ODN dose-dependently inhibited passive cutaneous anaphylaxis and histamine release from the mouse peritoneal mast cells (MPMC) activated by antidinitrophenyl (DNP) IgE. Northern blot analysis showed that the mast cells treated with antisense FcεRIα ODN exhibited no detectable levels of L-histidine decarboxylase mRNA after anti-DNP IgE stimulation, whereas the cells treated with sense FcεRIα ODN possessed significant amounts of this mRNA. Examination of the elevation of cAMP levels in MPMC following the activation with anti-DNP IgE demonstrated a significant rise in activated cells, but not in the antisense FcεRIα ODN-treated cells. Moreover, antisense FcεRIα ODN had a significant inhibitory effect on anti-DNP IgE-induced tumour necrosis factor-α production. Our results demonstrated that antisense FcεRIα ODN inhibited the IgE-mediated allergic reaction in vivo and in vitro.