Impairment of cognitive function is characteristic of untreated phenylketonuria in humans and in the pah^enu2 mouse model of phenylketonuria. We measured regional cerebral metabolic rate for glucose in the adult male pah^enu2 mouse to determine the effect of PKU on functional activity in brain and to discern what, if any, brain areas are affected. Our results demonstrate selective decreases (17–21%) in regions thought to be involved in executive function. Regions most significantly affected include prelimbic, anterior cingulate, orbital frontal and perirhinal cortex. Sensory and motor areas of cortex and hippocampus were remarkably unaffected.