The present studies show for the first time that, in vitro, fluorocarbon emulsions depress O2 uptake of tissue. This depression can be overcome totally or in part by use of O2 levels approaching 100% of the ambient atmosphere. Our studies also show that the diffusion coefficient for O2 in fluo-rocarbons and in fluorocarbon emulsions is dependent upon the O2 tension and falls as Po2 falls. However, due to the high O2 content of fluorocarbon, the O2 flux in fluoro-carbons is higher than that in control solutions. Therefore, the fall in diffusion coefficient cannot account for depression of O2 uptake in these studies. The cause of the depressed Qo2 remains unknown, but toxic-ity of fluorocarbon should be considered. The data suggest that if fluorocarbon is to be an efficacious blood substitute, high levels of inspired O2 will have to be maintained as long as high fluorocarbon levels exist in the circulatory system. Ms. Mary Allgood provided invaluable technical assistance. This study was supported by Grant Nos. HL 16643, HL 14251, and Virginia Lung Association Grants. © 1977, SAGE Publications. All rights reserved.