Drug-specific antibody Fab fragments have been used as a treatment for acute drug overdose. For some drugs, the required Fab dose may be very high (up to several g/kg) and may have adverse effects of its own. The current study evaluated the potential toxicity of an affinity purified sheep polyclonal Fab (TFab) directed at the two antidepressants desipramine (DMI) and nortriptyline. TFab 4 g/kg was administered to anesthetized rats i.v. over 10, 25 or 60 min, with or without a toxic dose of DMI. This high dose of TFab, which is in excess of that needed to reduce DMI toxicity, was used in order to exaggerate any adverse effects. In the absence of DMI, TFab produced minimal changes in the electrocardiographic QRS duration, systolic blood pressure and heart rate compared with control animals and was well tolerated. In the presence of DMI, groups receiving TFab as a 10 or 25 min infusion showed a therapeutic effect (lessening of DMI toxicity) over the first 60 min compared with the control group, but one of six animals in each of the TFab groups died prior to the end of the 180 min experiment. No control animals died, but progressive QRS prolongation and decreasing blood pressure toward the end of the experiment suggested that DMI toxicity was increasing over time. These data suggest that, when administered alone, very high doses of rapidly infused TFab are well tolerated. When administered with DMI, TFab is effective in initially reducing DMI toxicity. However, this dose of TFab may later aggravate DMI toxicity and/or the effects of prolonged anesthesia. The faster infusion rates were more effective in reducing DMI toxicity, but the rate of TFab infusion did not influence toxicity. Although the TFab dose used in this study is probably higher than would be required for use in humans, these data suggest that strategies to reduce and optimize the dose of TFab administered should be pursued.