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Statistical Parametric Mapping (SPM) is widely used for the quantitative analysis of brain images from 18F fluorodeoxyglucose positron emission tomography (FDG PET). SPM requires an initial step of spatial normalization to align all images to a standard anatomic model (the template), but this may lead to image distortion and artifacts, especially in cases of marked brain abnormalities. This study aimed at assessing a block-matching (BM) normalization algorithm, where most transformations are not directly computed on the overall brain volume but through small blocks, a principle that is likely to minimize artifacts.Large and/or small hypometabolic areas were artificially simulated in initially normal FDG PET images to compare the results provided by statistical tests computed after either SPM or BM normalization.Results were enhanced by BM, compared with SPM, with regard to (i) errors in the estimation of large defects volumes (about 2-fold lower) because of a lower image distortion, and (ii) rates of false-positive foci when numerous or extended abnormalities were simulated. These observations were strengthened by analyses of FDG PET examinations from epileptic patients.Results obtained with the BM normalization of brain FDG PET appear more precise and robust than with SPM normalization, especially in cases of numerous or extended abnormalities.