Depressions of regional cerebral metabolism beyond the epileptogenic zone have been demonstrated in patients with intractable temporal lobe epilepsy. However, their clinical relevance, and the causes of prefrontal metabolic asymmetries are less well understood. We investigated 96 temporal lobe epilepsy patients by FDG-PET and neuropsychological assessment who had a corresponding unilateral temporal hypometabolism, left hemisphere speech dominance, full scale IQ of > 70 and no extratemporal lesion in MRIs. The regional glucose metabolism was determined in each patient in homologous regions including prefrontal cortex, and normalized to whole brain metabolism. Regional differences of > 10% were regarded as asymmetrical. Prefrontal metabolic asymmetries were more frequent in patients with left temporal lobe epilepsy (21 left, six right) and a history of secondarily generalized seizures. A multivariate analysis of variance revealed a main effect for prefrontal metabolic asymmetry on neuropsychological 'frontal lobe measures', including verbal and performance intelligence measures. Prefrontal metabolic asymmetry was not related to 'measures of episodic memory', presence of psychiatric symptoms or frontal interictal epileptiform discharges. We conclude that prefrontal metabolic asymmetry is associated with cognitive impairment. Patients with temporal lobe epilepsy of the left speech dominant hemisphere and a history of secondarily generalized seizures are at considerable risk of developing prefrontal metabolic asymmetry.