Stroke-like Migraine Attacks after Radiation Therapy (SMART) syndrome is a rare complication of cranial irradiation. Radiation is well-known to impair vascular vessel architecture and function. We investigated the hypothesis of radiation-induced cerebral vascular reserve dysfunction as the underlying mechanism of SMART. Interictal cerebrovascular reactivity was investigated using Tc-99m hexamethylpropyleneamine oxime-SPECT and acetazolamide challenge in 3 patients. We found interictal hypoperfusion and normal cerebrovascular reactivity in all patients. Neither ictal restriction of the apparent diffusion coefficient nor MR angiography abnormalities were observed. These findings do not support a vascular mechanism in SMART syndrome. Postradiation neuronal dysfunction may be the underlying mechanism. Further investigations on larger series are needed to confirm this hypothesis.