BACKGROUND Recent data indicate that iron ions play a major role in lipid peroxidation, a hepatotoxic effect of acetaminophen (APAP). METHODS We investigated whether an iron chelator, deferoxamine (DFO), can protect against APAP-induced liver injury in vivo in rats. RESULTS DFO diminished the increase in serum alanine aminotransferase (ALAT) in a dose-dependent manner after APAP administration and also reduced mortality. Administration of 750 mg/kg APAP resulted in an increased ALAT (11,666 +/- 4633) after 8 h, and the mortality at 24 h was 88%. Pretreatment with 200 mg/kg DFO for 1 h significantly reduced ALAT (to 3406 +/- 894) and mortality (38%). DFO also attenuated histopathologic changes. Treatment with DFO depressed malondialdehyde formation by APAP without inhibiting glutathione depletion in the liver or reducing covalent binding of [3H]APAP to liver proteins. CONCLUSIONS These results indicate that the protective effect of DFO against APAP-induced liver injury may be attributable not to changes in APAP metabolism but to the chelation of iron, which can catalyze the generation of active oxygen species, in hepatocytes.