In line with the autoimmune hypothesis of schizophrenia we have tested in this study whether the commonly used neuroleptics, clozapine and haloperidol can also act as systemic immunosuppressants. Twenty one hospitalized chronic schizophrenic patients participated in the study. Five were free of neuroleptic treatment while the other 16 were under chronic treatment with either clozapine (n = 8), or haloperidol (n = 8). Fourteen age matched normal subjects served as the control group. Conventional in vitro mitogenic stimulation of peripheral blood lymphocytes with phytohaemagglutinin (PHA) indicated a clear suppression of responsiveness of approximately 50% in all treated patients. The PHA response of the untreated patients was virtually identical to that of the control group. The in vitro effect of haloperidol and clozapine on PHA stimulation of lymphocytes from normal subjects was determined by 3H-thymidine uptake and secretion of interleukin-2, interleukin-4 and interferon-gamma. Both clozapine and haloperidol suppressed thymidine incorporation and cytokine secretion at a drug concentration of above 1 microM, reaching full suppression at 50 microM. Similar suppressive effects of clozapine and haloperidol were also observed in mixed lymphocyte reaction of mouse lymphocytes. Assays with radioactive ligands indicated that clozapine is not incorporated into the lymphocytes but presumably exerts its action by binding to specific surface sites. The long term immune suppression induced by neuroleptic treatment may inhibit putative autoimmune responses against neurological sites and could thus act synergistically with the direct antagonistic action on brain receptors for the overt amelioration of psychotic behaviour.