It is generally accepted that patients with major depressive disorder have smaller hippocampus size compared to healthy people. However, it is still not known if this situation exists before the onset of the disease or is a result of the toxic mechanism created by the depression itself. The findings of the long-term follow–up studies of first–episode depressed patients might contribute to solve the ongoing problem. In this study, the hippocampus of 18 first–episode patients who were followed-up for 5 years, were compared with those of healthy controls. There were no volumetric differences among groups neither at the baseline nor after 5 years of follow–up. However, shape analyses, using high dimensional mapping methods, revealed regional structural changes in the head and tail of the hippocampal formation in CA1 and subiculum regions in patients at the follow–up. Furthermore, a significant negative correlation was found with the number of days in depression without antidepressant treatment in the CA1 region in the head and tail of the hippocampal formation bilaterally. The findings of this study support the hypothesis that pathophysiological processes of depression induce structural alterations in depressed patients.