A microwave-enhanced advanced oxidation process (MW-AOP) was used to treat thickened waste secondary sludge prior to anaerobic digestion (AD). A large amount of soluble chemical oxygen demand (SCOD) and volatile fatty acids (VFAs) was formed in the solution after pretreatment. Both single- and two-phase systems loaded up to 18.2 g volatile solids/(l day) while achieving high methane production, as well as high overall treatment efficiency. Both the upflow anaerobic blanket reactor and the continuous stirred tank reactor could operate at very short hydraulic retention times as short as 2 days without any evidence of souring. The results indicated that an acid reactor in the two-phase system was not required, due to very high levels of SCOD and VFAs produced in the MW-AOP-pretreated solution. As such, a single AD should be able to handle this easily biodegradable substrate following microwave pretreatment.