Perfluorochemicals (PFCs) are being widely developed for use as erythrocyte substitutes to carry oxygen to tissue in acute crises. Oxypherol, a commercially available PFC preparation commonly used for animal tests, reduces erythrocyte deformability in the presence of plasma. This undesirable effect further complicates oxygen delivery by erythrocytes. Our experiments indicate that one or more plasma proteins must be present to observe Oxypherol-induced reduction in erythrocyte deformability, but the latter is not protein specific. Neither platelet activation nor enhanced protein adsorption could account for the mechanism of altered erythrocyte flexibility. Using fluorine-19 NMR, it was found that a small amount of Oxypherol droplets is adsorbed on the surface of the erythrocytes. The amount of adsorbed droplets increases when Oxypherol is incubated with the erythrocytes in the presence of plasma, in parallel with a decrease in erythrocyte deformability. Therefore, it seems likely that the loss of deformability of the erythrocytes is caused by the adsorption of small Oxypherol droplets on the erythrocytes.