Background and Purpose: Glutamic acid decarboxylase antibodies (GAD‐Ab) are sometimes associated with chronic drug‐resistant focal epilepsy. Clinically, it may manifest as mesial temporal lobe epilepsy (mTLE), with GAD‐Ab patients difficult to distinguish. Therefore, the aim of this study is to compare brain metabolism of patients with mTLE and high serum titers of GAD‐Ab (>2000 UI/ml) to those with mTLE and hippocampal sclerosis (HS) and confirmed GAD‐ab negativity. Methods: Images from PET studies were normalized to an SPM 12 template. Voxel to voxel comparisons were made using a two‐sample one‐tailed t‐test. Results: In both patients with GAD‐Ab and controls (mTLE‐HS), hypometabolism in mesial temporal lobe areas was observed. When comparing the two groups, GAD‐Ab patients had statistically significant reduced metabolism in both insulae and medial inferior frontal‐hypothalamus area (p < 0.001). Conclusions: Hypometabolism in mesial temporal lobe areas together with hypometabolism in insulae and medial inferior frontal‐hypothalamus may be characteristic of patients with epilepsy and GAD‐ab. This PET pattern could be a useful diagnostic tool to identify GAD‐Ab patients. [ABSTRACT FROM AUTHOR]