OBJECTIVE: Although subtraction ictal SPECT coregistered to MRI (SISCOM) is clinically useful in epilepsy surgery evaluation, it does not determine whether the ictal-interictal subtraction difference is statistically different from the expected random variation between 2 SPECT studies. We developed a statistical parametric mapping and MRI voxel-based method of analyzing ictal-interictal SPECT difference data (statistical ictal SPECT coregistered to MRI [STATISCOM]) and compared it with SISCOM. METHODS: Two serial SPECT studies were performed in 11 healthy volunteers without epilepsy (control subjects) to measure random variation between serial studies from individuals. STATISCOM and SISCOM images from 87 consecutive patients who had ictal SPECT studies and subsequent temporal lobectomy were assessed by reviewers blinded to clinical data and outcome. RESULTS: Interobserver agreement between blinded reviewers was higher for STATISCOM images than for SISCOM images (κ = 0.81 vs κ = 0.36). STATISCOM identified a hyperperfusion focus in 84% of patients, SISCOM in 66% (p < 0.05). STATISCOM correctly localized the temporal lobe epilepsy (TLE) subtypes (mesial vs lateral neocortical) in 68% of patients compared with 24% by SISCOM (p = 0.02); subgroup analysis of patients without lesions (as determined by MRI) showed superiority of STATISCOM (80% vs 47%; p = 0.04). Moreover, the probability of seizure-free outcome was higher when STATISCOM correctly localized the TLE subtype than when it was indeterminate (81% vs 53%; p = 0.03). CONCLUSION: Statistical ictal SPECT coregistered to MRI (STATISCOM) was superior to subtraction ictal SPECT coregistered to MRI for seizure localization before temporal lobe epilepsy (TLE) surgery. STATISCOM localization to the correct TLE subtype was prognostically important for postsurgical seizure freedom.