We conducted two xenon Xe 133 inhalation regional cerebral blood flow (rCBF) studies to clarify earlier findings of dorsolateral prefrontal cortex (DLPFC) dysfunction in medication-free patients with chronic schizophrenia. In the first study, 24 neuroleptic-treated patients and 25 normal controls underwent three rCBF procedures, first while at rest, then during the Wisconsin Card Sort (WCS), which tests DLPFC cognitive function, and during a number-matching task that controlled for aspects of the WCS-rCBF experience not specifically related to DLPFC. The results were qualitatively identical to those previously reported for medication-free patients. In the second study, rCBF was determined while 18 medication-free patients and 17 normal control subjects each performed two versions of a visual continuous performance task (CPT). No differences in DLPFC blood flow between the two groups were found during either CPT condition. These data suggest that DLPFC dysfunction in schizophrenia is independent of medication status and not determined simply by state factors such as attention, mental effort, or severity of psychotic symptoms. Dysfunction of DLPFC appears to be a cognitively linked physiologic deficit in this illness.