The neuronal circuit disturbances that drive interictal and ictal epileptiform discharges remains elusive. Using a combination of extraoperative macro- and micro-electrode interictal recordings in six presurgical patients during non-rapid eye movement (REM) sleep we found that, exclusively in the seizure onset zone, fast ripples (FR; 200-600Hz), but not ripples (80-200 Hz), frequently occur <300 msec before an interictal intracranial EEG (iEEG) spike with a probability exceeding chance (bootstrapping, p<1e-5). Such FR events are associated with higher spectral power (p<1e-10) and correlated with more vigorous neuronal firing than solitary FR (generalized linear mixed-effects model, GLMM, p<1e-3) irrespective of FR power. During the iEEG spike that follows a FR, action potential firing is lower than during a iEEG spike alone (GLMM, p<1e-10), reflecting an inhibitory restraint of iEEG spike initiation. In contrast, ripples do not appear to prime epileptiform spikes. We next investigated the clinical significance of pre-spike FR in a separate cohort of 23 patients implanted with stereo EEG electrodes who underwent resections. In non-REM sleep recordings, sites containing a high proportion of FR preceding iEEG spikes correlate with brain areas where seizures begin more than solitary FR (p<1e-5). Despite this correlation, removal of these sites does not guarantee seizure freedom. These results are consistent with the hypothesis that FR preceding EEG spikes reflect an increase in local excitability that primes EEG spike discharges preferentially in the seizure onset zone and that epileptogenic brain regions are necessary, but not sufficient, for initiating interictal epileptiform discharges.