This study compares the effects of two neuroleptic drugs with different pharmacologic characteristics (thiothixene and haloperidol) on cerebral glucose utilization in chronic schizophrenic inpatients. Positron emission tomographic (PET) scans were obtained from all subjects in a neuroleptic-free condition and again after 4-6 weeks of neuroleptic treatment. Eight subjects were treated with thiothixene and 12 with haloperidol. Thiothixene and haloperidol had different metabolic effects. For example, all thiothixene-treated subjects showed increased whole brain glucose utilization; all but one haloperidol-treated subject showed decreased utilization. Different patterns of relative prefrontal and striatal metabolism were also observed. These results highlight the importance of controlling for the effects of neuroleptic treatment and indicate the difficulty of interpreting data from studies with complex or poorly defined drug regimens.