The general distribution of 3H-haloperidol was studied in mice by means of whole body autoradiography. Extensive accumulation and retention was observed in the melanin containing tissues. In the albino animals uptake was low in the corresponding tissues. Impulse counting of excised tissue pieces showed a maximum concentration in the pigmented eyes 24 hr after a single intravenous injection. In the pigmented eyes, about 1/5 of the radioactivity at 24 hr still remained 90 days after administration. In vitro, haloperidol was found to be bound to beef-eye melanin and dopamine melanin (structurally similar to the melanin present in the pigmented nerve cells in the human substantia nigra). The total binding capacity of beef-eye melanin was approximately twice that of dopamine melanin. Beef-eye melanin bound haloperidol to an extent twice that earlier reported for chlorpromazine and chloroquine, while the binding strengths were of about the same magnitude. Due to its high melanin affinity it is most probable that haloperidol accumulates extensively in the pigmented neurons of the substantia nigra in patients on long term therapy. Other compounds with melanin affinity such as phenothiazine derivatives and manganese are known to produce irreversible extrapyramidal disorders, degeneration and depigmentation of the pigmented nerve cells in the substantia nigra. In conclusion the melanin affinity may be an important factor in the pathogenesis of haloperidol induced tardive dyskinesia.