The purpose of this study was to describe the methodology necessary for simultaneous recording of intracranial EEG (ICEEG) and magnetoencephalography (MEG) and to assess the sensitivity of whole-head MEG versus depth electrode EEG in the detection and localization of epileptic spikes. Interictal MEG and depth electrode activities from the temporal mesial and occipital lobes were simultaneously recorded from four candidates for epilepsy surgery. Implanted depth electrodes identified neocortical and mesial structures of ictal onset. Interictal spikes detected by these same depth electrodes were compared with simultaneous MEG events. MEG detections of ICEEG spikes, ICEEG versus MEG spike amplitudes, number of ICEEG contacts involved in the spike, and anatomic locations of MEG equivalent current dipoles were analyzed. MEG detected and localized 95% of the neocortical spikes, but only 25% to 60% of spikes from mesial structures. Mesial temporal spikes resulted in lower MEG spike amplitudes, when compared with neocortical spikes. Equivalent current dipoles of MEG spikes localized to the ictal onset zones in all four patients. MEG can detect and localize interictal epileptiform spikes that are recorded from depth electrodes in both neocortical and mesial structures, despite the lesser amplitude of spikes of mesial origin.