ObjectiveTo assess whether arterial spin labeling perfusion images of healthy controls can enhance ictal single‐photon emission computed tomography analysis and whether the acquisition of the interictal image can be omitted.MethodsWe developed 2 pipelines: The first uses ictal and interictal images and compares these to single‐photon emission computed tomography and arterial spin labeling of healthy controls. The second pipeline uses only the ictal image and the analogous healthy controls. Both pipelines were compared to the gold standard analysis and evaluated on data of individuals with epilepsy who underwent ictal single‐photon emission computed tomography imaging during presurgical evaluation between 2010 and 2022. Fifty healthy controls prospectively underwent arterial spin labeling imaging. The correspondence between the detected hyperperfusion and the postoperative resection cavity or the presumably affected lobe was assessed using Dice score and mean Euclidean distance. Additionally, the outcomes of the pipelines were automatically assigned to 1 of 5 concordance categories.ResultsInclusion criteria were met by 43 individuals who underwent epilepsy surgery and by 73 non‐surgical individuals with epilepsy. Compared to the gold standard analysis, both pipelines resulted in significantly higher Dice scores and lower mean distances (p < 0.05). The combination of both provided localizing results in 85/116 cases, compared to 54/116 generated by the current gold standard analysis and the ictal image alone produced localizing results in 60/116 (52%) cases.InterpretationWe propose a new ictal single‐photon emission computed tomography protocol; it finds relevantly more ictal hyperperfusion, and halves the radiation dose in about half of the individuals. ANN NEUROL 2024