A new model for mechanically induced red blood cell damage is presented. Incorporating biophysical insight at multiple length scales, the model couples flow-induced deformation of the cell membrane (similar to 10 mu m) to membrane permeabilization and hemoglobin transport (similar to 100 nm). We estimate hemolysis in macroscopic (above similar to 1 mm) 2-D inhomogeneous blood flow by computational fluid dynamics (CFD) and compare results with literature models. Simulations predict the effects of local flow field on RBC damage, due to the combined contribution of membrane permeabilization and hemoglobin transport. The multiscale approach developed here lays a foundation for a predictive tool for the optimization of hydrodynamic and hematologic design of cardiovascular prostheses and blood purification devices. (c) 2014 American Institute of Chemical Engineers AIChE J, 60: 1509-1516, 2014