PURPOSE: The rhinal cortex, comprising the entorhinal (ErC) and perirhinal (PrC) cortices, is one component of the limbic system that may be affected in patients with epilepsy and other temporal lobe pathologies. This study extended quantitative examination of the limbic system through development and validation of volumetric protocols to measure the ErC and PrC. METHODS: Volumes were calculated from MRI studies using ANALYZE 7.5 and based on detailed anatomical definitions developed for the study. Subjects were 61 temporal lobe epilepsy patients with mesial temporal sclerosis (MTS: 33 left, 28 right) and 20 neurologically normal controls. Inter-rater reliabilities for the ErC and PrC volume protocols were found to be high (range 0.86-0.92). RESULTS: Ipsilateral hippocampal volume was reduced in patients with MTS, while contralateral volume did not differ significantly from controls. In the patients, rhinal cortex volumes were reduced as a function of laterality of disease. The pattern of correlations between ErC and PrC differed between disease groups. Hippocampal and rhinal cortex volumes were not significantly correlated. A significant four-way interaction was found between side of MTS, hemisphere, structure and handedness. CONCLUSIONS: This quantitative study demonstrates reliable in vivo evidence of morphometric changes in ErC and PrC in a substantial number of patients with unilateral MTS. The relationship observed between handedness, structure and disease status may suggest a role for cerebral dominance in modulating the expression of MTS.