Several studies have demonstrated that structural brain change is detectable in the hippocampus in both patients, with schizophrenia and major depression. Only few studies, however, compared both clinical disease entities directly and no larger study has tried to take different disease stages into account. The objectives of this study are to investigate whether hippocampal volumes are reduced in patients with schizophrenia and those with major depression with the same duration of illness compared to healthy controls and to assess further changes at different disease stages. A total of 319 inpatients and healthy controls were enrolled and investigated with magnetic resonance imaging (MRI). Hippocampal volumes were measured using the segmentation software BRAINS. Bilateral hippocampal volume reductions were detected in both schizophrenic and depressed patients compared to healthy control (HC) subjects. Although younger, schizophrenic (SZ) patients showed in their MRI scans significant bilaterally reduced hippocampal volumes compared to patients with major depression. Although the hippocampal reductions were similar at the onset of symptomatic manifestation of both diseases, there was a further significant reduction of the left hippocampus in the recurrently ill SZ subgroup. The data suggest rather dynamic structural brain alterations in schizophrenia compared to major depression. Here, the presented application of the comparative neuroscience approach, by the use of large neuroimaging MRI databases, seems highly valuable. In the field of psychiatry, with its still controversial operationalized descriptive diagnostic entities, the cross-nosological approach provides a helpful tool to better elucidate the still unknown brain pathologies and their underlying molecular mechanisms beyond a single nosological entity.