Abnormalities in limbic-thalamic-cortical networks are hypothesized to modulate human mood states. In the present study differences in hippocampal volumes of patients with a first episode of depression, recurrent major depression and healthy control subjects were examined with high-resolution magnetic resonance imaging (MRI). Male patients with a first episode of major depression had a significantly smaller left hippocampal volume than male control subjects. Also, these patients had a significant left-right asymmetry in hippocampal volume. Female patients showed no significant alterations in hippocampal volumes. The results support the hypothesis that the hippocampus plays an important role in the pathophysiology of the early phase of major depression, especially for male patients. Implications for the neurodevelopmental and the neurodegenerative model of hippocampal change are discussed.