Background: The view that schizophrenia is a brain dis- ease particularly involving decrements in gray matter is supported by findings from many imaging studies. How- ever, it is unknown whether the (progressive) loss of tis- sue affects the brain globally or whether tissue loss is more prominent in some areas than in others. Methods: Magnetic resonance whole brain images were acquired from 159 patients with schizophrenia or a schizo- phreniform disorder and 158 healthy subjects across a 55-year age span. Gray matter density maps were made and analyzed using voxel-based morphometry. Results: Compared with healthy subjects, decreases in gray matter density were found in the left amygdala; left hip- pocampus; right supramarginal gyrus; thalamus; (orbito) frontal, (superior) temporal, occipitotemporal, precune- ate, posterior cingulate, and insular cortices bilaterally in patients with schizophrenia or schizophreniform disor- der. Compared with healthy subjects, increases in gray mat- ter density were exclusively found in the right caudate and globus pallidus in patients with schizophrenia or schizo- phreniform disorder. A group-by-age interaction for den- sity was found in the left amygdala, owing to a negative regression slope of gray matter density on age in the left amygdala in patients compared with healthy subjects. Conclusions: Gray matter density is decreased in dis- tinct focal areas in the brains of patients with schizophre- nia or schizophreniform disorder. The decreased density in the left amygdala is more pronounced in older patients with schizophrenia. Arch Gen Psychiatry. 2001;58:1118-1125