It has been suggested that schizophrenia is primarily a prefrontal-temporal-limbic circuitry disorder. Further, it has been argued that primary neurologic vulnerability to the illness is established only during early stages of brain development and is not progressive. We tested the hypothesis of whether brain volume losses in prefrontal and temporal-limbic regions have occurred either before or after brain growth was hypothesized to be complete in schizophrenia. Nineteen chronic schizophrenic patients and 19 age- and sex-matched normal controls underwent magnetic resonance imaging (MRI). All scans were segmented into gray and white matter and cerebrospinal fluid (CSF) compartments for the frontal and temporal lobes and posterior cerebral hemispheres. Multivariate analysis of variance was used to analyze absolute intracranial cerebrum and subregion volumes, i.e., gray, white and CSF, absolute tissue (i.e., gray plus white) volumes, and tissue to intracranial volume (TCV) ratios. Patients showed significant intracranial volume reductions only in the frontal lobes but highly significantly lower TCV ratios (i.e., greater relative tissue loss) in all three major regions. It is suggested that the observed decreases in frontal intracranial volumes reflect a pathologic process in schizophrenia that impacted the frontal regions before brain growth was complete. We hypothesize that the generalized lower patient TCV ratios are attributable to a process that affected the whole cerebrum over a time period after brain volume had reached its maximum levels.