These studies were conducted to determine the effect of anesthetic drugs on tissue perfusion and O2 supply in the brain with focal cerebral edema. Using an open cranium preparation, we studied the effects of isoflurane (I; 1 minimum alveolar anesthetic concentration), of fentanyl (F; 0.5–1 μg·kg−1 ·min−1), or of thiopental (T; 32.5 mg·kg−1·h−1) on regional cerebral blood flow (rCBF) and regional brain tissue Po2 in albino rabbits (n = 6 per group) with a focal brain lesion (cold injury). The doses of anesthetics were sufficient to suppress no-ciception. rCBF (H2 clearance) and tissue Po2 (multi-wire surface electrode) were studied adjacent to and distant from the lesion. Cerebral hyperemia developed immediately after trauma in all groups, although the flow increase did not attain statistical significance. rCBF was subsequently reduced by about 25% in the vicinity of the lesion. Distant from the trauma, a continuing hyperemia (+30%) was later observed in animals with isoflurane, whereas rCBF was decreased then by 10%-20% in animals with fentanyl, or was unchanged with thiopental. Brain tissue Po2 was increased with isoflurane in areas distant from the lesion, but decreased with fentanyl. However, with thiopental, the Po2 level had already been lowered before trauma with a subsequent tendency toward normalization. The heterogeneity of the tissue Po2 in fentanyl anesthesia, as well as the increased frequency of hypoxic Po2 values with thiopental, might have resulted from micro-circulatory disturbances. Thus, although isoflurane seemed to facilitate hyperemia with an increased O2 supply to the brain, fentanyl tended to induce the opposite response. Although these properties suggest the potential to manipulate perfusion and O2 supply in cerebral ischemia or hyperemia after head injury, the effects of such measures on intracranial pressure, neurologic status, and outcome have yet to be proven.