To investigate the effect of fractionated whole-brain irradiation on nonhuman primates, 6–9-year-old male rhesus monkeys were irradiated with 40 Gy delivered as two 5-Gy fractions/week for 4 weeks. Cognitive function was assessed 5 days/week for 4 months prior to fractionated whole-brain irradiation and for 11 months after irradiation using a Delayed-Match-to-Sample (DMS) task at both low and high cognitive loads. Local rates of cerebral glucose metabolism were measured prior to and 9 months after irradiation using [¹⁸F]-2-deoxy-2-fluoro-d-glucose positron emission tomography. Low cognitive load trials did not reveal a significant reduction in performance until 7 months after irradiation; performance then declined progressively. In high cognitive load trials, the initial impairment was observed ∼1 month after irradiation. This was followed by a transient recovery period over the next 1–2 months, after which performance declined progressively through 11 months after irradiation. Nine months after irradiation, glucose uptake during the DMS task was decreased in the cuneate and prefrontal cortex and was increased in the cerebellum and thalamus compared with the levels prior to irradiation. Results from this pilot study suggest that the radiation-induced changes in cognition and brain metabolism observed in rhesus monkeys may be similar to those observed in brain tumor patients receiving brain irradiation.