Cassava alcohol residue was first pretreated by hydrothermal reaction. Hydrothermal pretreatment was optimized by RSM for co-utilization of C-5 and C-6 sugars. The maximum xylose yield and the highest enzymatic digestibility were not obtained at the same conditions. Optimum pretreatment conditions were at 193 °C, with 11.4% solids and for 51 min. The optimal theoretical ethanol production was 69.5 mg/g raw materials by co-utilization of C-5 and C-6 sugars.