A robust fault detection scheme for a class of nonlinear systems with uncertainty is proposed. The proposed approach utilizes robust control theory and parameter optimization algorithm to design the gain matrix of fault tracking approximator (FTA) for fault detection. The gain matrix of FTA is designed to minimize the effects of system uncertainty on residual signals while maximizing the effects of system faults on residual signals. The design of the gain matrix of FTA takes into account the robustness of residual signals to system uncertainty and sensitivity of residual signals to system faults simultaneously, which leads to a multiobjective optimization problem. Then, the detectability of system faults is rigorously analyzed by investigating the threshold of residual signals. Finally, simulation results are provided to show the validity and applicability of the proposed approach.