The Sylvian fissure region gathers lateral frontotemporal cortices and subcortical structures that are frequently disturbed in patients with mood disorders. We have investigated possible CSF space changes in this brain region in severe melancholic depression. Fifty-seven patients and 37 control subjects received three-dimensional MRI. CSF volumes were obtained for cerebral CSF, lateral ventricles, and both Sylvian fissure regions. As a group, patients showed a significant CSF space enlargement that was prominent around the Sylvian fissure, particularly in the left hemisphere. Likewise, evident leftward asymmetry was more frequent in the patient group (patients 31.6%, controls 2.7%). The combination of CSF space enlargement and the pattern of Sylvian CSF asymmetry predicted the patient condition with 62.2% specificity and 82.5% sensitivity. We conclude that, in the context of a broad severity spectrum of imaging alterations in severe melancholic depression, asymmetrical CSF space enlargement may be evident in the Sylvian fissure region.