AbstractThe piriform cortex (PC) is located at the junction of the temporal and frontal lobes. It is involved physiologically in olfaction as well as memory and plays an important role in epilepsy. Its study at scale is held back by the absence of automatic segmentation methods on MRI. We devised a manual segmentation protocol for PC volumes, integrated those manually derived images into the Hammers Atlas Database (n= 30) and used an extensively validated method (multi‐atlas propagation with enhanced registration, MAPER) for automatic PC segmentation. We applied automated PC volumetry to patients with unilateral temporal lobe epilepsy with hippocampal sclerosis (TLE;n= 174 includingn= 58 controls) and to the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI;n= 151, of whom with mild cognitive impairment (MCI),n= 71; Alzheimer's disease (AD),n= 33; controls,n= 47). In controls, mean PC volume was 485 mm3on the right and 461 mm3on the left. Automatic and manual segmentations overlapped with a Jaccard coefficient (intersection/union) of ~0.5 and a mean absolute volume difference of ~22 mm3in healthy controls, ~0.40/ ~28 mm3in patients with TLE, and ~ 0.34/~29 mm3in patients with AD. In patients with TLE, PC atrophy lateralised to the side of hippocampal sclerosis (p< .001). In patients with MCI and AD, PC volumes were lower than those of controls bilaterally (p< .001). Overall, we have validated automatic PC volumetry in healthy controls and two types of pathology. The novel finding of early atrophy of PC at the stage of MCI possibly adds a novel biomarker. PC volumetry can now be applied at scale.