Fractionated whole-brain irradiation (fWBI), used to treat brain metastases, often leads to neurologic injury and cognitive impairment. The cognitive effects of irradiation in nonhuman primates (NHP) have been previously published; this report focuses on corresponding neuropathologic changes that could have served as the basis for those effects in the same study. Four rhesus monkeys were exposed to 40 Gy of fWBI [5 Gy × 8 fraction (fx), 2 fx/week for four weeks] and received anatomical MRI prior to, and 14 months after fWBI. Neurologic and histologic sequelae were studied posthumously. Three of the NHPs underwent cognitive assessments, and each exhibited radiation-induced impairment associated with various degrees of vascular and inflammatory neuropathology. Two NHPs had severe multifocal necrosis of the forebrain, midbrain and brainstem. Histologic and MRI findings were in agreement, and the severity of cognitive decrement previously reported corresponded to the degree of observed pathology in two of the animals. In response to fWBI, the NHPs showed pathology similar to humans exposed to radiation and show comparable cognitive decline. These results provide a basis for implementing NHPs to examine and treat adverse cognitive and neurophysiologic sequelae of radiation exposure in humans.