This study tested the hypothesis that the estimate of the apparent diffusion coefficient (ADC; an index of cytotoxic edema) of water is a reliable pathophysiological index of the viability of ischemic brain tissue. CBF, the partition volume of water (PVW; an index of vasogenic edema), cerebral metabolic rate of oxygen (CMRO2), and of glucose (CMR(glc)) were measured before and after permanent middle cerebral artery occlusion (MCAO) or reperfusion with positron emission tomography (PET) in pigs. Then, the ADC was measured by diffusion-weighted magnetic resonance imaging (DW-MRI) and was compared with physiological variables obtained by PET and with histological findings. Both after permanent MCAO and reperfusion, the ADC was significantly correlated to the CMRO2 and CMR(glc). The sequential decrease of ADC was also correlated to the sequential reduction of CMRO2 in relation to the residual CBF after permanent MCAO. The infarction coincided with a threshold CMRO2 of 50% of the contralateral value and a threshold ADC of 75% of the contralateral value, respectively. The PVW was decreased in relation to the magnitude of residual CBF after MCAO, whereas it was transiently increased in the severely ischemic lesions below 75% of the contralateral ADC value after reperfusion. Thus, the ADC is a reliable pathophysiological index which allows therapy to be tailored to the condition of individual patients in clinical practice.