Abstract The P300 is a cognitive event-related potential partially generated by the amygdala/hippocampus complex, the most common source of temporal lobe epilepsy (TLE). In order to test the hypothesis that scalp P300 amplitude is reduced ipsilateral to the epileptogenic focus in TLE, we performed a prospective study of 15 subjects with TLE and compared the lateralizing ability of scalp P300 to interictal EEG. P300 asymmetries in TLE were compared with asymmetries in a control group. P300 amplitude was significantly attenuated ipsilateral to the epileptic focus. P300 amplitude reduction correctly lateralized the focus in 82% of the cases ( p = 0.02). We conclude that scalp P300 accurately lateralizes the epileptogenic focus in TLE. Further studies are needed to define the potential role of P300 in the presurgical evaluation of TLE.