Understanding the three-dimensional anatomy of the perihippocampal fissures (PHFs) can be helpful in making the correct diagnosis of diseases of the mesial temporal lobe. Disorders of the parenchyma and cerebrospinal fluid spaces are reflected by specific changes in the PHFs. A marker for Alzheimer disease and mesial temporal sclerosis is atrophy of the hippocampus and associated dilatation of the PHFs. This finding is best visualized on coronal magnetic resonance images but can and should be appreciated on routine computed tomographic scans. Hydrocephalus is characterized by dilatation of the temporal horn of the lateral ventricle without dilatation of the transverse fissure and its extensions. Normal-pressure hydrocephalus can usually be distinguished from Alzheimer disease on the basis of the pattern of dilatation of the PHFs. Understanding the anatomy of the PHFs often makes it possible to better characterize the extents of intra- and extraaxial tumors of the mesial temporal lobe.