A retrospective magnetic resonance (MR) imaging study was performed in 41 right-handed patients with presumed mesial sclerosis who underwent surgery for medically intractable, complex partial seizures of temporal lobe origin. The ability of each of five different MR imaging-based tests to lateralize the seizure disorder was determined. In order of decreasing usefulness the tests were (a) hippocampal formation (HF) volume measurements, (b) visual grading of MR images for unilateral HF atrophy, (c) anterior temporal lobe (ATL) volume measurements, (d) visual grading of MR images for unilateral ATL atrophy, and (e) evidence of unilateral medial temporal lobe signal intensity abnormalities on long repetition time MR images. A right-side minus left-side volume (designated DHF) was obtained to quantify unilateral HF atrophy with a single number. Patients with right-sided seizures had a median DHF of -0.4 cm3, while those with left-sided seizures had a median DHF of 0.8 cm3, consistent with atrophy of the HF ipsilateral to the seizure disorder. Conservative volumetric threshold values (-0.2 cm3 and 0.6 cm3), separating individual DHF measurements into right-side abnormal, indeterminate, and left-side abnormal, allowed DHF measurements to be 76% sensitive and 100% specific for correct seizure lateralization.