Sulfate radicals produced by ultrasonic activation of persulfate (PS) or sulfate were applied to disintegrate sludge flocs and extracellular polymeric substances (EPSs). The pretreatment facilitated the production of volatile fatty acids (VFAs) and hydrogen from subsequent anaerobic fermentation, yielding a potential method for improving the utilization of sulfate-containing waste-activated sludge (WAS). Sulfate radicals produced using ultrasound (US) in the presence of PS/sulfate showed a synergetic effect of advanced oxidation on WAS pretreatment. Among the three types of pretreatment (US, US + Sulfate, and US + PS), US + PS pretreatment was the most favoured for chemical oxygen demand (COD) solubilization, protein release, and sludge disintegration under a US density of 1.5 W/mL. Tightly bound EPS (TB-EPS) could be effectively disintegrated, and organic compounds were transformed into loosely bound EPS and soluble EPS. Unexpected COD consumption by excessive free radicals was also observed, when increasing the ultrasonic energy input (e.g. to 12 W/mL), towards a positive role for sludge disintegration and subsequent anaerobic fermentation. It was found that small particles (0.1-0.5 mu m) from released organics could be preferentially overoxidized. An appropriate low ultrasonic strength initiated attack on the polymeric substances in WAS by the produced radicals, which TB-EPS could be primary target.