Structural neuroimaging has been used to correlate lesional patterns with the cognitive profile of patients with multiple sclerosis (MS), especially for "frontal" dysfunction. However, a clear-cut anatomical explanation has yet to be found for the long-term memory deficit which is a hallmark of MS cognitive impairment. We have used PET to measure regional cerebral glucose metabolism (rCMRglc) in a group of 15 MS patients with involvement of verbal and/or spatial long-term memory. These patients were compared with 10 normal controls and 13 MS patients unimpaired on all neuropsychological tests. Relative to the controls, MS patients with memory deficits showed a significant bilateral reduction of rCMRglc in the hippocampus, cingulate gyrus, thalamus, associative occipital cortex, and cerebellum. Direct comparisons between patients with memory deficits and the group of unimpaired MS patients showed a metabolic reduction in the left thalamus and in both hippocampi. Seven of the memory-impaired patients also had neuropsychological signs of frontal dysfunction. These patients were compared with patients who had isolated memory deficit. Here we observed a further metabolic reduction in a number of brain regions including bilateral prefrontal cortex, inferior parietal cortex, and basal ganglia. Our findings indicate that hypometabolism of thalamic and deep cortical gray structures of the temporal lobe is associated with episodic memory dysfunction in MS. On the other hand, pathological performance on tests designed to assess frontal functions was associated with widespread reduction of glucose metabolism.