When fixed doses of haloperidol or perphenazine were used in two separate studies, we found that psychotic males with a prior history of psychotogenic drug use had a poorer early neuroleptic response even in the early stages of their psychotic disorder than psychotic males who had not previously used significant amounts of psychotogenic drugs. Relative neuroleptic refractoriness may be characteristic of some dual diagnosis patients at the beginning of their illness. Antecedent psychotogenic drug use may contribute to the development of psychosis and to relative neuroleptic refractoriness by means of effects upon dopaminergic mechanisms.