Cerebrocirculatory responses to total perfluorocarbon (FC-43)-for-blood replacement (Hct less than 1%) were studied in anesthetized, ventilated rats breathing 100% O2. Changes in total and regional cerebral blood flow (CBF) were measured using the radiolabeled-microsphere technique. The data were compared with two control groups of hemoglobin-circulated animals; one group was exposed to arterial hypoxia (arterial PO2 = 40 Torr) and the other to isovolemic hemodilution with Krebs-Henseleit-albumin (KHA) solution (mean Hct = 11%). Exchange transfusion with FC-43 doubled total and regional CBF, causing preferential flow increases to the cortex and cerebellum. Estimated cerebrovascular resistance fell to 50% of the preexchange value. Both hemodilution and hypoxia control experiments produced CBF responses similar to those obtained in FC-43 animals. Although calculated arterial O2 contents in all three groups of animals were similar, blood viscosity was normal in hypoxic rats and reduced in KHA and FC-43 animals. Since arterial and cerebrovenous PO2s were both high in fluorocarbon-circulated rats, our results suggest that decreased O2 content and perhaps lower viscosity of the circulating fluorocarbon were responsible for increases in CBF required to maintain sufficient delivery of O2 to the brain.