Objective: We sought evidence of a hereditary component for hippocampal sclerosis (HS) by determiningwhether close relatives of probandswith temporal lobe epilepsy (TLE) withHS also had asymptomatic HS or subtle variation in hippocampal morphology. Methods: First-degree relatives from 15 families in which probands had TLE with HS and 32 age- and sex-matched controls were included in the study. Left and right hippocampal volumes and T2 relaxometry were measured using 3-tesla MRI. Results: Thirty-two asymptomatic first-degree relatives and 3 relatives with a history of seizures or epilepsy were studied. None of the first-degree relatives had HS on visual analysis and T2 relaxation times were normal, excluding the presence of HS. Mean hippocampal volume was smaller (6.4%) in asymptomatic relatives (2.94±6 0.27 cm3, 95% confidence interval 5 2.87-3.01) than in controls (3.14±6 0.22 cm 3, 95% confidence interval 5 3.09-3.19, p < 0.005); the effect was greater in relatives of probands with a positive family history of epilepsy. The relatives also had more asymmetric hippocampi (asymmetric index 0.92±6 0.05) than controls (0.96 6±0.03, p 5 0.001). Conclusions: Small asymmetric hippocampi in healthy relatives are likely to represent a familial developmental variant that may predispose to the formation of TLE with HS. The underlying histopathology of these small hippocampi is unknown. This observationmay provide an imaging marker for future studies seeking susceptibility genes for HS.