This study investigates the neurophysiological basis of EEG feedback for patients with epilepsy. Brain areas are identified that become hemodynamically deactivated when epilepsy patients, trained in EEG self-regulation, generate positive slow cortical potentials (SCPs). Five patients were trained in producing positive SCPs, using a training protocol previously established to reduce seizure frequency in patients with drug refractory epilepsy. Patients attempted to produce positive SCP shifts in a functional magnetic resonance imaging (fMRI) scanner. Two patients were able to reliably produce positive SCP shifts. When these successful regulators were prompted to produce positive SCPs, blood oxygen level-dependent (BOLD) response indicated deactivation, in comparison to a control state, around the recording electrode, frontal lobe, and thalamus. Unsuccessful regulators' BOLD response indicated no deactivation in cortical areas proximal to the active electrode. No thalamic deactivation was found in poor regulators. Decreased seizure frequency from SCP training may be the result of positively reinforced inhibition in cortical areas proximal to active electrode placement, the frontal cortex, and the thalamus.