Objective: To compare composite subtraction ictal single-photon emission computed tomography coregistered to magnetic resonance imaging (also known as SISCOM) patterns between right and left medial temporal-onset seizures to document neuroanatomical involvement in perfusion patterns. Design: A retrospective comparative survey. Setting: Epilepsy monitoring unit in a tertiary care referral center. Participants: Subjects with temporal lobe epilepsy (TLE) who underwent ictal single-photon emission computed tomography studies. Main Outcome Measures: Comparison of ictal perfusion pattern changes in subjects with right and left temporal seizures. Results: Composite subtraction ictal single-photon emission computed tomography coregistered to magnetic resonance images showed similar regions of hyperperfusion change in the ipsilateral anteromedial temporal-corpus striatum-insula region in both groups. In the midbrain reticular formation, there was a significant difference in hyperperfusion between the left and rightTLEgroups. In addition, the right, but not the left, TLE group shows contralateral hypoperfusion of the temporoparietal junction. Conclusions: While anteromedial temporal-corpus striatum-insula perfusion patterns are similar, there are brainstem and hemispheric perfusion pattern differences in right and left TLE seizures, confirming pathophysiological differences between the groups. These findings help define neuronal network involvement in TLE seizures, and may explain the differences in clinical symptoms of right and left TLE seizures.