The red cell deformation under oscillatory shear stress was studied. Shear stress was sinusoidally modulated between 8 and 32 dyn/cm2, thus, the extent of cellular deformation altered sinusoidally. At a low modulation frequency (less than 1.8 Hz), intact red cells perfectly responded to the shear stress applied on cells, and they could deform as much as the deformation in stationary shear flow. Above 2 Hz, the cellular deformation could not follow changes in shear stress along up-phase in the shear stress cycle. As decreasing the intracellular hemoglobin concentration, the cellular response to oscillatory shear stress became better. Treatment of cells with low concentrations of diamide impaired the response of intact cells to oscillatory shear stress, but unaffected the response of partially hemolyzed cells. These data suggest that the cellular response to oscillatory shear stress is determined by the cytoskeletal structure and the intracellular viscosity.