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Summary: Objective: Imaging activated glutamate N‐methyl‐D‐aspartate receptor ion channels (NMDAR‐ICs) using positron emission tomography (PET) has proved challenging due to low brain uptake, poor affinity and selectivity, and high metabolism and dissociation rates of candidate radioligands. The radioligand [18F]GE‐179 is a known use‐dependent marker of NMDAR‐ICs. We studied whether interictal [18F]GE‐179 PET would detect foci of abnormal NMDAR‐IC activation in patients with refractory focal epilepsy. Methods: Ten patients with refractory focal epilepsy and 18 healthy controls had structural magnetic resonance imaging (MRI) followed by a 90‐min dynamic [18F]GE‐179 PET scan with simultaneous electroencephalography (EEG). PET and EEG findings were compared with MRI and previous EEGs. Standard uptake value (SUV) images of [18F]GE‐179 were generated and global gray matter uptake was measured for each individual. To localize focal increases in uptake of [18F]GE‐179, the individual SUV images were interrogated with statistical parametric mapping in comparison to a normal database. Additionally, individual healthy control SUV images were compared with the rest of the control database to determine their prevalence of increased focal [18F]GE‐179 uptake. Results: Interictal [18F]GE‐179 PET detected clusters of significantly increased binding in eight of 10 patients with focal epilepsy but none of the controls. The number of clusters of raised [18F]GE‐179 uptake in the patients with epilepsy exceeded the focal abnormalities revealed by the simultaneously recorded EEG. Patients with extensive clusters of raised [18F]GE‐179 uptake showed the most abnormal EEGs. Significance: Detection of multiple foci of abnormal NMDAR‐IC activation in 80% of our patients with refractory focal epilepsy using interictal [18F]GE‐179 PET could reflect enhanced neuronal excitability due to chronic seizure activity. This indicates that chronic epileptic activity is associated with abnormal NMDAR ion channel activation beyond the initial irritative zones. [18F]GE‐179 PET could be a candidate marker for identifying pathological brain areas in patients with treatment‐resistant focal epilepsy. [ABSTRACT FROM AUTHOR]