We designed a semiautomated method for the objective detection of abnormal regions of tracer accumulation in the brain. The purpose of the present study was to examine the diagnostic performance of this method by applying it to patients with clinically intractable epilepsy of unilateral origin; they underwent [F-18] deoxyglucose positron emission tomography (PET) prior to surgical resection of epileptic foci. A semiautomated method for assessment of asymmetries in the brain cortex was developed that compares activity concentrations in homotopic cortical areas. When these differences exceeded a predefined threshold, the areas with lower activity were marked and 3-dimensional surface rendered images were created to guide placement of intracranial electrodes (ECoG) followed by surgical resection. The normal amount of asymmetry between small (0.5-0.7 cm2) homotopic cortical regions was determined as 5.9 +/- 4.0% (mean +/- SD). The false-positive fraction was determined for cutoff thresholds of 1 SD (10%), 1.5 SD (12%), and 2 SD (15%) outside the mean and was found to be 89, 44, and 0%, respectively. The obtained sensitivity-specificity pairs for correct localization of epileptogenic lobes based on the ECoG results were best for the 15% threshold (80/94%, accuracy 0.90). This objective PET method allows the accurate determination of cortical asymmetries, and it proved to be highly efficient in guiding epilepsy surgery.