Immune functions in the brain are associated with psychiatric illness and temporary alteration of mental state. Microglia, the principal brain immunologic cells, respond to changes in the internal brain milieu through a sequence of activated states, each with characteristic function and morphology. To assess a possible association of frontal white matter pathology with suicide, we stained autopsy brain tissue samples from 11 suicide and 25 nonsuicide subjects for ionized calcium-binding adapter molecule 1, cluster of differentiation 68, and myelin. Groups were matched by age, sex, and psychiatric diagnosis. We classified ionized calcium-binding adapter molecule 1-immunoreactive cells based on shape, immunoreactivity to cluster of differentiation 68, and association with blood vessels to obtain stereologic estimates of densities of resting microglia, activated phagocytes, and perivascular cells. We found no effect of psychiatric diagnosis but 2 statistically significant effects of suicide: 1) The dorsal-ventral difference in activated microglial density was reversed such that, with suicide, the density was greater in ventral prefrontal white matter than in dorsal prefrontal white matter, whereas in the absence of suicide, the opposite was true; and 2) with suicide, there was a greater density of ionized calcium-binding adapter molecule 1-immunoreactive cells within or in contact with blood vessel walls in dorsal prefrontal white matter. These observations could reflect a mechanism for the stress/diathesis (state/trait) model of suicide, whereby an acute stress activates a reactive process in the brain, either directly or by compromising the blood-brain barrier, and creates a suicidal state in an individual at risk. They also indicate the theoretical potential of imaging studies in living vulnerable individuals for the assessment of suicide risk. Further studies are needed to investigate specific phenotypes of perivascular cells and blood-brain barrier changes associated with suicide.