The aim of this prospective study was to investigate whether decreased cerebrovascular reactivity to acetazolamide, as determined by single-photon emission computed tomography (SPECT), is an independent predictor of the 5-year risk of subsequent stroke in patients with symptomatic major cerebral artery occlusion. Cerebrovascular reactivity to acetazolamide in the middle cerebral artery (MCA) territory ipsilateral to the occluded artery was determined on the basis of two different methodologies: cerebral blood flow (CBF) percent change obtained quantitatively from xenon-133 (133Xe) SPECT, and asymmetry index (AI) percent change obtained qualitatively from N-isopropyl-p-[123I]-iodoamphetamine (IMP) SPECT. Seventy patients with unilateral internal carotid artery or MCA occlusion were divided into two groups within each SPECT methodology (normal or decreased CBF percent change and AI percent change) and followed up for 5 years. Cumulative recurrence-free survival rates for patients with decreased CBF percent change were significantly lower than for those with normal CBF percent change (P = 0.0205). There was no significant difference in cumulative recurrence-free survival rates between patients with decreased AI percent change and those with normal AI percent change. Only decreased CBF percent change was a significant independent predictor of stroke recurrence (P = 0.0051). The present study demonstrated that decreased cerebrovascular reactivity to acetazolamide determined quantitatively by 133Xe SPECT is an independent predictor of the 5-year risk of subsequent stroke in patients with symptomatic major cerebral artery occlusion, and that the qualitative method using 123I-IMP SPECT is a poor predictor of the risk of subsequent stroke in this type of patient.