Computational fluid dynamics (CFD) has been a viable and effective way to predict hydraulic performance, flow field, and shear stress distribution within a blood pump. We developed an axial blood pump with CFD and carried out a CFD-based shape optimization of the diffuser blade to enhance pressure output and diminish backflow in the impeller-diffuser connecting region at a fixed design point. Our optimization combined a computer-aided design package, a mesh generator, and a CFD solver in an automation environment with process integration and optimization software. A genetic optimization algorithm was employed to find the pareto-optimal designs from which we could make trade-off decisions. Finally, a set of representative designs was analyzed and compared on the basis of the energy equation. The role of the inlet angle of the diffuser blade was analyzed, accompanied by its relationship with pressure output and backflow in the impeller-diffuser connecting region.