A decrease in the cerebral blood flow (CBF) response to acetazolamide may indicate an increase in cerebral blood volume (CBV) caused by reduced perfusion pressure in patients with major cerebral artery steno-occlusive lesions. However, a decrease in cerebral metabolic rate of oxygen (CMRO(2)) caused by ischemic changes may also decrease the CBF response to acetazolamide by decreasing the production of carbon dioxide. The purpose of this study was to determine whether the values of CBV and CMRO(2) are independent predictors of the CBF response to acetazolamide in major cerebral arterial occlusive disease. We used positron emission tomography to study 30 patients with major cerebral artery steno-occlusive lesions. The CBF response to acetazolamide was assessed by measuring baseline CBF and CBF 10 min after an intravenous injection of 1 g of acetazolamide. Multivariate analysis was used to test the independent predictive value of the CBV and CMRO(2) at baseline with respect to the percent change in CBF during acetazolamide administration. Both increased CBV and decreased CMRO(2) were significant and independent predictors of the reduced CBF response to acetazolamide. CBV accounted for 25% of the variance in the absolute change in CBF during acetazolamide administration and 42% of the variance in the percent change in CBF, whereas CMRO(2) accounted for 19% and 4% of the variance, respectively. In patients with major cerebral arterial occlusive disease, a decrease in CMRO(2) may contribute to the reduced CBF response to acetazolamide, although an increase in CBV appears to be the major contributing factor.