We evaluated whether mesial temporal lobe epilepsy (MTE) and neocortical temporal lobe epilepsy (NTE) can be distinguished on electroclinical grounds. One hundred and twenty-two consecutive MTE (n = 86) and NTE (n = 36) patients were included in this prospective study. All patients underwent prolonged EEG-video monitoring and high resolution magnetic-resonance imaging (MRI). MTE was defined as epilepsy with purely mesial temporal lesion in the absence of extramesial temporal pathology, based on pre-operative MRI or post-operative histology. NTE was defined as neocortical temporal MRI lesions, depth recorded neocortical temporal seizure onset and lack of mesial temporal lesions on MRI or histology. One thousand two hundred and fourty-nine epileptic seizures were analyzed. Congenital malformation (NTE 19% versus MTE 3%, P < 0.01), nonspecific auras (NTE 25% versus MTE 8%, P < 0.001) and early clonic activity following automatisms (NTE 22% versus MTE 8%, P < 0.03) were more frequent in NTE. In contrast, a history of febrile seizures (MTE 29% versus NTE 3%, P < 0,001), abdominal auras (MTE 62% versus NTE 33%, P < 0.005) and contralateral hand dystonia (MTE 43% versus NTE 22%, P < 0.03) were more often documented in MTE. Interictal epileptiform discharges in MTE occurred predominantly (> 67%) over the ipsilateral mesial temporal regions (MTE 65% versus NTE 33%, P < 0.001). No MTE patient had lateral neocortical temporal spike predominance (NTE 22%, P < 0.001). Multiple logistic regression revealed that a history of febrile seizures, abdominal auras, contralateral dystonic posturing and predominance of ipsilateral mesial temporal spikes point to MTE, with an accuracy of 73% (PPV 81%, NPV 70%). Analyzing clinical and EEG features, particularly the distribution of interictal epileptiform discharges, helps to differentiate between MTE and NTE.