Clinical markers of the adequacy of cerebral perfusion may be misleading. The effects of isolated changes in systemic blood pressure, Paco2, Pao2, and cerebral edema on cerebral blood flow and oxygenation are relatively well known, but the quantitative effects of interactions between these factors are not easily calculated. We aimed to investigate the relationship between these factors using a computational model. Using a validated, quantitative, computational model of cerebral blood flow, the simulated effects of changes in systemic blood pressure (50-180 mm Hg), Paco2 (33-55 mm Hg [4.3-7.3 kPa]), Sao2 (0.8-1.0), and cerebral edema (0%-10% increase in intercapillary distance) on middle cerebral artery flow velocity (MCAFV), brain tissue oxygenation (Pbo2), and jugular venous oxygen saturation (Sjo2) were recorded. Individual markers of adequacy of cerebral perfusion (MCAFV, Sjo2, and Pbo2 behave in accordance with clinical data with single changes in the parameters studied: the lower limit of autoregulation for MCAFV and Sjo2 lies around 60 mm Hg mean arterial blood pressure. In our model, the upper limit of autoregulation lies around 170 mm Hg, but is much less distinct for Sjo2 and Pbo2 than for MCAFV. Significant cerebral ischemia appears unlikely to occur with isolated physiological changes according to our simulation. However, the combination of hypotension, hypoxia, and edema makes ischemia much more likely in this model. Edema increases the Sjo2:Pbo2 gradient, confirming that diffusion-limited oxygen delivery may make Sjo2 values falsely reassuring. The simulated effects of pathophysiological changes on cerebral oxygenation and perfusion have been quantitatively described. Significant cerebral ischemia is predicted in the presence of two or more physiological derangements. Cerebral edema is associated with an increased gradient between Sjo2 and Pbo2.