The hippocampus plays a central role in the generation and propagation of seizures in patients with complex partial seizures. Hippocampal sclerosis (HS) is a common structural abnormality in patients with refractory epilepsy. The aim of this study was to quantify diffusion in the hippocampus in patients with epilepsy to evaluate the diffusion changes associated with HS. We scanned 20 subjects (14 patients and 6 controls) with a 1.5T magnetic resonance (MR) system using a cardiac-gated, navigated spin-echo diffusion-weighted sequence. Hippocampal ADC measurements were performed on maps of the ADC measured in three orthogonal directions labeled x, y, and z. The mean ADC (ADCav) and an anisotropy index (AI) were calculated. Hippocampi which fulfilled the MR criteria for HS had a higher ADCav (p < 0.001) and a lower AI (p=0.04) than normal appearing hippocampi in patients and hippocampi in controls. These results imply a loss of structural organization in sclerotic hippocampi and an expansion of the extracellular space. Quantitative measurements of diffusion can be used as an independent parameter for the identification and characterization of abnormal hippocampi in epilepsy.