We investigated whether the lack of therapeutic response to long-term and adequate neuroleptic treatment was due to a failure to achieve a blockade of cerebral dopamine receptors. Six chronic schizophrenic and medicated patients (DSM-III-R diagnosis, paranoid or disorganized type) were assessed with the Present State Examination and the Brief Psychiatric Rating Scale. According to the Chouinard Rating Scale there were little extrapyramidal symptoms, although no anticholinergic drugs were given. Plasma levels of the neuroleptics were determined and found in the therapeutic range or higher. Dopamine D2-receptor occupancy was determined with positron emission tomography using 11C-methylspiperone as ligand. There was a more than 95% blockade of the D2 receptors in the striatum. These results indicate that the lack of therapeutic response and extra-pyramidal side effects cannot be attributed to an incomplete blockade of cerebral D2 receptors and that the pathogenetic role of these receptors can be questioned in therapy-resistant schizophrenic patients.