A combined NaOH-microwave (MW) pretreatment process was studied in order to investigate the effects of NaOH-MW pretreated thickened waste activated sludge (TWAS) on anaerobic digestion. In the NaOH-MW pretreatment studies, Uniform design was successfully applied to determine the relationship of TWAS solubilization to environmental conditions (NaOH dose, target temperature, and MW holding time) and to establish the mathematical model describing the solubilization degree to changes in these variables. The maximum solubilization ratio (85.1%) of volatile suspended solids (VSS) could be achieved at 210° with 0.2 g-NaOH/g-SS and 35 min holding time. The biochemical methane potential (BMP) tests showed that all digesters fed with pretreated TWAS improved the methane production compared to control system, and the optimal conditions, at 170° with 0.05 g-NaOH/g-SS and 1 min holding time, were suggested for NaOH-MW pretreatment of TWAS. In spite of the increase in the soluble chemical oxygen demand concentration and decrease in the dewaterability of digested sludge, the semi-continuous reacter fed with the pretreated TWAS without neutralization was stable and gave higher organics reductions and methane yields compared to the control.