Long-term neuroleptic medication of schizophrenic patients induces extrapyramidal motor side effects, of which tardive dyskinesia (TD) is the most severe. The etiology of TD is still obscure. Recently, it was suggested that abnormal iron metabolism may play a crucial role in neuroleptic-induced dopamine D2 receptor super-sensitivity. The apparent relationship between neuroleptics and iron is further supported by the increase of iron in the basal ganglia of patients with TD. We now report on the ability of neuroleptic to alter the blood-brain barrier in the rat and to potentiate the normally limited iron transport into the brain. Thus, chronic treatment of rats with chlorpromazine and haloperidol facilitated 59Fe3+ uptake into brain cells. In contrast, clozapine, an atypical antipsychotic neuroleptic with little extrapyramidal motor side effects, caused iron sedimentation in brain blood vessels with no sign of detectable iron in the cells. Moreover, chronic treatment with chlorpromazine and haloperidol caused a 43% and 24% reduction, respectively, in liver nonheme iron, whereas clozapine induced an 81% increase. The apparent different potentials of chlorpromazine, haloperidol, and clozapine to increase iron transport into the brain from its peripheral stores may be linked to the severity of extrapyramidal motor side effects they induce and to the pathophysiology of TD.