Amodiaquine is an antimalarial drug that has been associated with adverse reactions which may be immune mediated. Specific IgG anti-amodiaquine antibodies were detected after administration of the drug to rats (269 μmol/kg for 4 days), using an enzyme-linked immunosorbent assay employing amodiaquine conjugated to metallothionein as an antigen. A positive immune response was observed regardless of the route of administration, but the magnitude of the response in terms of antibody titre was in the order intraperitoneal administration > intramuscular administration > oral administration. Hapten inhibition experiments with structurally related drugs defined the specificity of the antibody which appears to recognize a conjugate of amodiaquine quinone imine and cysteine residues present in protein. Amodiaquine was converted to a protein-reactive species by activated human polymorphonuclear leucocytes in vitro, and this may provide a mechanism for immunogen formation in vivo. A humoral immune response was observed with doses of amodiaquine that did not produce either direct hepatotoxicity or leucopenia. Thus an animal model has been developed with which to investigate the toxicological consequences of amodiaquine immunogenicity.