Effects of protein and NaCl concentrations in plasma on red blood cell (RBC) deformability were studied using fresh human blood and a 5-microns Nuclepore filtration test. The protein and salt concentrations were varied by diluting the plasma with saline and adding crystalline NaCl to the fluids, respectively. The mean pore passage time of the RBCs, which was measured as an index of the deformability, increased with increasing plasma protein and NaCl concentrations. A marked interdependence was observed; the relation of RBC deformability with plasma protein was accentuated by an increase in plasma NaCl, whereas the effect of increasing plasma NaCl was diminished by a decrease in plasma protein. It is suggested that the RBC-protein interaction which is modified by the fluid ionic strength plays a dominant role in producing these characteristic changes in RBC deformability with protein and salt contents in the plasma. An analysis is made of the cell-protein interaction; the electric repulsive and van der Waals attractive forces are calculated with a result that the protein adsorption on a RBC increases with increasing fluid ionic strength above normal. This analysis, furthermore, provides information on the surface charge distribution on a RBC.