OBJECTIVE This study examined the effect of neuroleptic treatment on indexes of dopamine and serotonin function in schizophrenic patients. We hypothesized that neuroleptic treatment would be effective by changing dopamine and serotonin function and/or by altering their interaction. METHODS Lumbar cerebrospinal fluid (CSF) concentrations of the metabolites of dopamine (homovanillic acid, [HVA]) and serotonin (5-hydroxyindoleacetic acid, [5-HIAA]) were measured after a minimum drug-free period of two weeks and again after five weeks of treatment with haloperidol, 20 mg/d orally. Psychiatric symptoms were rated within one day of CSF sampling. METHODS Sixteen schizophrenic and three schizoaffective male inpatients. RESULTS Neuroleptic treatment significantly raised HVA concentrations and significantly increased the ratio between HVA and 5-HIAA. The increase in HVA was not related to symptomatic improvement, whereas the increase in the HVA/5-HIAA ratio was significantly correlated with reduction in overall symptomatology. CONCLUSIONS These findings suggest that the increase in HVA is relative to 5-HIAA, and not the absolute increase in HVA, that is related to symptomatic improvement. This, in turn, suggests that changing dopamine function relative to serotonin function, rather than changing dopamine per se, is associated with the therapeutic effect of haloperidol. Exploring serotonin-dopamine interactions in schizophrenia may be more informative than examining each system in isolation.