The aim of the present study was to determine whether central benzodiazepine receptor binding potential (BRBP)/cerebral blood flow (CBF) or a combination of CBF and cerebrovascular reactivity (CVR) to acetazolamide on single-photon emission computed tomography (SPECT) more accurately detects misery perfusion, indicating elevation of absolute value of oxygen extraction fraction (OEF) on positron emission tomography (PET), in patients with unilateral major cerebral artery occlusive diseases. In 84 patients, OEF, CBF, CVR to acetazolamide, and BRBP were assessed using ¹⁵O-PET and N-isopropyl-p-[¹²³I]-iodoamphetamine and [¹²³I]-iomazenil SPECT, respectively. A region of interest was automatically placed in the middle cerebral artery territory using a 3-dimensional stereotactic region of interest template. Sensitivity, specificity, and positive and negative predictive values for the affected side-to-contralateral side asymmetry on SPECT-BRBP/CBF to detect the abnormally elevated PET-OEF in the affected hemisphere were 100%, 86.4%, 66.7%, and 100%, respectively. Area under the receiver operating characteristic curve in detecting the abnormally elevated PET-OEF in the affected hemisphere did not differ between analysis of the combination of SPECT-CBF and SPECT-CVR in the affected hemisphere (0.89; 95% confidence interval, 0.80-0.94) and that of the affected side-to-contralateral side asymmetry on SPECT-BRBP/CBF (0.93; 95% confidence interval, 0.86-0.97). The combination of the 3 detected abnormally elevated PET-OEF with 97.0% specificity and 90.0% positive predictive value. The accuracy of central BRBP/CBF asymmetry on SPECT is equivalent to that of the combination of CBF and CVR to acetazolamide on SPECT for detecting misery perfusion in patients with unilateral major cerebral artery occlusive disease.