Current therapy for cardiotoxicity due to tricyclic antidepressant (TCA) overdose is often ineffective in seriously poisoned patients. We studied the effect of a drug-specific antibody fragment on TCA cardiotoxicity in rats. Animals received anti-TCA F(ab′)2 2.0 g/kg i.v. over 10 min starting 15 min after administration of a toxic dose of desipramine (DMI). This anti-TCA F(ab′)2 dose was 36.9% of the molar DMI dose in terms of binding sites. Anti-TCA F(ab′)2 infusion had no adverse effects and rapidly reduced DMI induced QRS prolongation compared with control F(ab′)2 (23 ± 14 vs 71 ± 11% QRS prolongation at the end of infusion, P < 0.001). This beneficial effect lasted for the min duration of the study. Markedly enhanced DMI binding in serum after anti-TCA F(ab′)2 was demonstrated by a 48-fold increase in the total DMI concentration over controls and a reduction in the fraction of unbound DMI (44.5 ± 19.4 vs 0.7 ± 0.2%). Anti-TCA F(ab′)2 reduced the DMI concentration in brain but not in other organs. We conclude that anti-TCA F(ab′)2 substantially reduces DMI cardiotoxicity in rats, and does so rapidly enough to be of potential clinical benefit for patients with DMI overdose. Because only a small fraction of the DMI dose was bound by antibody, these data suggest that antibody fragment doses considerably less than equimolar to the DMI dose may be effective in treating DMI cardiotoxicity.