Objectives: There is compelling evidence that pathological high-frequency oscillations (HFOs), called fast ripples (FR, 150-500Hz), reflect abnormal synchronous neuronal discharges in areas responsible for seizure genesis in patients with mesial temporal lobe epilepsy (MTLE). It is hypothesized that morphological changes associated with hippocampal atrophy (HA) contribute to the generation of FR, yet there is limited evidence that hippocampal FR-generating sites correspond with local areas of atrophy. Methods: Interictal HFOs were recorded from hippocampal microelectrodes in 10 patients with MTLE. Rates of FR and ripple discharge from each microelectrode were evaluated in relation to local measures of HA obtained using 3-dimensional magnetic resonance imaging (MRI) hippocampal modeling. Results: Rates of FR discharge were 3 times higher in areas of significant local HA compared with rates in nonatrophic areas. Furthermore, FR occurrence correlated directly with the severity of damage in these local atrophic regions. In contrast, we found no difference in rates of ripple discharge between local atrophic and nonatrophic areas. Interpretation: The proximity between local HA and microelectrode-recorded FR suggests that morphological changes such as neuron loss and synaptic reorganization may contribute to the generation of FR. Pathological HFOs, such as FR, may provide a reliable surrogate marker of abnormal neuronal excitability in hippocampal areas responsible for the generation of spontaneous seizures in patients with MTLE. Based on these data, it is possible that MRI-based measures of local HA could identify FR-generating regions, and thus provide a noninvasive means to localize epileptogenic regions in hippocampus.