The effect of elevated shear stress upon cellular trauma has been studied for many years, but the effect of long-term cyclic stress trauma on hemorheology has never been explored systematically. This study investigated sublytic trauma of red blood cells (RBCs) caused by repeated exposure to shear stress. A suspension of bovine blood was throttled through a capillary tube (inner diameter 1 mm and length 70 mm) connected to a recirculating flow loop. Samples were withdrawn every 30 min to measure deformability and characteristic time. The deformability of the cell was measured microscopically by observing the shape of the cell during the shear flow. It was found that cyclic shear irreversibly stiffened the cell membrane while the effect was not so much as that of continuous shear. The cell deformability was dramatically reduced by 73% when the stress of 300 Pa was applied for 288 s, while it was 7% under 90 Pa. These results elucidate the need for improved models to predict cellular trauma within the unsteady flow environment of mechanical circulatory assist devices.