Progressive decline of memory functions has been observed in patients with chronic medication-resistant epilepsy. The progression likely relates to the effects of epileptiform discharges, seizures, and medications on the processes of encoding and retrieval. The goal of the study described here was to use functional MRI (fMRI) to examine the effects of chronic epilepsy on verbal recognition memory. We enrolled 12 patients with medication-resistant epilepsy (5 with right and 7 with left hemispheric seizure onset) and 18 healthy controls matched for age, gender, and handedness. Subjects underwent fMRI at 3 T using a word recognition task during which they had to recall if words presented during scanning were words they had learned prior to scanning. Although we noted many similarities in the fMRI activation patterns between the subjects with epilepsy and the healthy subjects in areas typically involved in memory processing, testing of the interaction effects for target-foil differences between groups revealed several differences in activation including the right insula, the left cuneus, and the bilateral subgenual anterior cingulate cortex (ACC). In patients with epilepsy, these regions exhibited greater activation for targets than foils, but in healthy subjects the difference was reversed (right insula), absent (left cuneus), or included deactivation to target words (pregenual ACC). These differences were seen despite similar performance during the memory task, suggesting that activations observed in these additional regions may represent compensatory processes for verbal recognition memory that are induced by chronic brain injury related to recurrent seizures. © 2008 Elsevier Inc. All rights reserved.