The nonuniform ac current distribution among the multilayer conductors in a high-temperature superconducting (HTS) cable reduces the current capacity and increases the ac loss. Various numerical simulation techniques and optimization methods have been applied in structural optimization of HTS cables. While the existence of fluctuation in design variables or operation conditions has a great influence on the cable quality, in order to eliminate the effects of parameter perturbations in design and to improve the design efficiency, a robust optimization method based on design for six sigma (DFSS) is presented in this paper. The optimization results show that the proposed optimization procedure can not only achieve a uniform current distribution, but also improve significantly the reliability and robustness of the HTS cable quality, comparing with those by using the particle swarm optimization.