Abstract: A robust optimization method for computing RBE-weighted dose based on the mixed beam model is proposed to reduce the influence of range and setup uncertainties on dose distribution in carbon-ion radiotherapy. Firstly, a probabilistic robust model was established and the objective function was expressed using the quadratic function. Then two treatment plans were designed regarding to physical absorbed dose and RBE-weighted dose. Finally, the conjugate gradient method was adopted to find the respective optimal solutions so as to make the actual dose distribution across the target volume and organ at risk(OAR) meet the dose requirements as much as possible. The C-shaped model was utilized to evaluate the effectiveness of this method. Compared with the conventional dose optimization method based on the planning target volume(PTV), the robust treatment planning based on physical absorbed dose made \Delta D_95\text% reduce 10.0 cGy in the clinical target volume(CTV), and the \Delta D_5\mathrm\text% and \Delta D_\mathrmm\mathrma\mathrmx parameters of the OAR decreased by 21.50 and 35.97 cGy respectively, indicating that the robustness of the plans has been greatly improved. Besides, the robust treatment planning based on RBE-weighted dose showed that \Delta D_95\text% reduced by 14.00 cGy(RBE) in the CTV while \Delta D_5\text% \;\mathrma\mathrmn\mathrmd\mathrm \;\Delta D_\rm max in the OAR reduced by 19.00 and 26.28 cGy(RBE), respectively. These results illustrate that the robust optimization method not only reduced the variation of biological dose in the CTV, but also reduced the hot spots of biological dose in the OAR. Collectively, the robust optimization method for RBE-weighted dose based on the mixed beam model could effectively enhance the robustness of carbon-ion radiotherapy treatment planning while sparing OAR simultaneously.