Accumulated evidence suggests the involvement of vascular factors in late-onset depression. Late-onset depression has characteristics of poor outcome, cognitive decline, and high prevalence rather than early-onset depression. The aim of the present study was to determine whether or not the functional hypofrontality--that is, hypoperfusion and hypometabolism in the frontal lobes-seen in late-onset depression is a trait-dependent abnormality of microvascular regulation. This study was conducted on 10 patients with remitted late-onset major depressive disorder (MDD) and 10 healthy volunteers matched for vascular factors and subcortical, or white matter, hyperintensities (WMH). Using near-infrared spectroscopy combined with magnetic resonance imaging, we investigated the microvascular reactivity in the prefrontal cortex during a cognitive task and during carbon dioxide (CO(2)) inhalation. Activation of the prefrontal cortex during the cognitive task was significantly less in patients as compared with controls, although task performance was not significantly different between the two groups. In the patients, a tendency of negative correlation between the reduced prefrontal activation during a cognitive task and the severity of hyperintensity in periventricular region was observed. Vasomotor reactivity to CO(2) inhalation was significantly lower in the patients than in the controls. Although there was no significant association between the activation during the cognitive and that during the CO(2) inhalation task, the present results suggest that prefrontal microvascular dysregulation as shown by NIRS is involved in the pathophysiological basis of functional hypofrontality in late-onset depression. This finding will provide a new framework for the development of diagnostic methods, treatments, and preventive strategies against late-onset depression.