Objective – To compare the sensitivity of ictal 99mTc-HMPAO single photon emission computed tomography (SPECT) with interictal 18F-fluorodeoxyglucose positron emission tomography (PET) in localization of the epileptogenic focus in patients with medically intractable complex partial seizures (MI-CPS). Material and methods – Retrospective analysis was performed on patients with MI-CPS who underwent anterior temporal lobectomy from January 1993 onwards when PET became available to us for clinical studies at the Indiana University Medical Center. There were 38 female and 29 male patients (total=67) with MI-CPS, 10 to 55.5 years of age (mean 31) and duration of their epilepsy from 1-46 years (mean 21). Interictal PET was evaluated for evidence of focal hypometabolism and ictal SPECT for focal perfusion abnormality (hyperperfusion or hypoperfusion) by visual analysis. Results – Both Ictal SPECT and interictal FDG-PET studies were obtained in 36 patients with MI-CPS. PET showed definite hypometabolism in 30 and questionable hypometabolism in an additional two patients. Ictal SPECT correctly localized the seizure focus in 27 patients by demonstrating ictal hyperperfusion whereas in one the hyperperfusion was falsely localized. In an additional seven patients the ictal SPECT provided probable localization by demonstrating ictal hypoperfusion in the appropriate temporal lobe. The sensitivity of ictal SPECT and interictal PET was 34/36 and 32/36, respectively, the difference was not statistically significant (χ2y=0.18, DF=1, P=0.67). In six of the 36 patients the two tests were complementary to each other in providing localizing information. Conclusion – Ictal SPECT and interictal PET are equally sensitive and reliable techniques in localizing the epileptogenic focus in patients with MI-CPS. They play a critical role in providing localization in MRI negative patients allowing surgical resection to be undertaken in many without additional invasive electrographic monitoring.