UNLABELLED: (18)F-4-(2'-methoxyphenyl)-1-[2'-(N-2-pyridinyl)-p-fluorobenzamido]-ethyl-piperaz ine ((18)F-MPPF) PET has proved to be a sensitive technique in the presurgical evaluation of patients with drug-resistant temporal lobe epilepsy (TLE), but a significant proportion of visually detected abnormalities failed to be detected by standard statistical parametric mapping (SPM) analysis. This study aimed at describing a voxel-based method for computing interhemispheric asymmetric index (AI) using statistical software and applying and validating the clinical relevance of this method for analyzing asymmetries of (18)F-MPPF PET images in patients with drug-resistant TLE. METHODS: (18)F-MPPF PET scans of 24 TLE patients who achieved an Engel class I outcome after epilepsy surgery and of 41 controls were analyzed visually, with standard SPM, and by computing voxel-based AIs. Both SPM methods were assessed using 2 different statistical thresholds (P < 0.05, corrected at the cluster level, and P < 0.05, familywise error (FWE) corrected at the voxel level). Sensitivity and specificity of each method were estimated and compared using McNemar tests. RESULTS: The sensitivity of AI analysis to detect decreases of (18)F-MPPF binding potential ipsilateral to the epileptogenic lobe was 92% (P < 0.05, corrected at the cluster level) and 96% (P < 0.05, familywise error corrected at the voxel level), whereas specificity (defined as the congruence between the localization of the voxel associated with the greatest z score and that of the epileptogenic zone) was 88% at both thresholds. AI analysis was significantly more sensitive (P < 0.05) and specific (P < 0.005) than standard SPM analysis, regardless of the applied threshold. AI analysis also proved to be more sensitive than visual analysis. CONCLUSION: AI analysis of (18)F-MPPF PET was more sensitive and specific than previous methods of analysis. This noninvasive imaging procedure was especially informative for the presurgical assessment of patients presenting with clinical histories atypical of mesial TLE or with normal brain MRI results.