Interferon-alpha commonly induces depressive symptoms in clinical populations; however, the mechanism by which this occurs is unclear. Recent studies suggest that the degeneration of axons containing serotonin and noradrenaline is involved in the pathophysiology of depression. The present immunohistochemical study shows that the density of serotonergic axons decreased in the ventral medial prefrontal cortex and amygdala in the interferon-alpha-treated animals. Additionally, interferon-alpha induced decreases in the density of noradrenergic axons in the dorsal medial prefrontal cortex, ventral medial prefrontal cortex, and dentate gyrus. These results support the hypothesis that long-term administration of interferon-alpha causes the degeneration of monoaminergic axons in specific brain regions, which might be associated with depressive symptoms occurring in interferon-alpha-treated patients.