Intravascular volume expansion has been successfully employed to promote blood flow in ischemic brain regions. This effect has been attributed to both decreased blood viscosity and increased cardiac output resulting from volume expansion. The physiological mechanism by which changes in cardiac output would affect cerebral blood flow (CBF), independent of blood pressure variations, is unclear, but impaired cerebral autoregulation is believed to play a role. In order to evaluate the relationship between cardiac output and CBF when autoregulation is either intact or defective, 135 simultaneous measurements of cardiac output (thermodilution method) and CBF (by the 133Xe inhalation or intravenous injection method) were performed in 35 severely head-injured patients. In 81 instances, these measurements were performed after manipulation of blood pressure with phenylephrine or Arfonad (trimethaphan camsylate), or manipulation of blood viscosity with mannitol. Autoregulation was found to be intact in 55 of these cases and defective in 26. A wide range of changes in cardiac output occurred after administration of each drug. No correlation existed between the changes in cardiac output and the changes in CBF, regardless of the status of blood pressure autoregulation. A significant (40%) increase in CBF was found after administration of mannitol when autoregulation was defective. These data support the hypothesis that, within broad limits, CBF is not related to cardiac output, even when autoregulation is impaired. Thus, the effect of intravascular volume expansion appears to be mediated by decreased blood viscosity rather than cardiac output augmentation.