The pathophysiology of stroke-like episodes in MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is uncertain. We studied a 24-year-old man with MELAS who had fluent aphasia and right hemianopia. Magnetic resonance imaging and computed tomography showed a large infarction in the parietal, temporal, and occipital lobes. We performed serial planar 133Xe regional cerebral blood flow studies and single-photon emission computed tomography. Fifteen and 26 days after the stroke-like episode, there was generalized hyperperfusion, highest in infarcted areas. Four and 8 months after the stroke-like episode, the brain was still hyperemic, with highest flow in noninfarcted tissue. Reactivity to CO2 was less than normal within the infarct at 26 days but improved thereafter. In the noninfarcted region, vasomotor reactivity was impared at 4 months, when resting flows were at their peak. We observed generalized cerebral hyperemia and fluctuating CO2 reactivity in MELAS, possibly a consequence of local lactic acid production. In addition, this case suggests that nonquantitative functional imaging may be misleading in MELAS.