The combined polyferric sulfate (PFS) coagulation with Fenton‐like was investigated for treating nondegradable antibiotic fermentation wastewater. The experimental results indicated that 62.2% of chemical oxygen demand (COD) and 66.7% of color were removed, under the optimum conditions of coagulant dosage 200 mg/L, stirring time 12 min, and settling time 1 h. From the PFS characterization by means of Fourier transform infrared, X‐ray diffraction, scanning electron microscope, and transmission electron microscope, it was believed that PFS coagulation was a mechanism including adsorption, neutralization of charged particles, and bridging between colloid particles. In addition, optimal conditions of Fenton‐like process were determined to be H2O2 dosage of 150 mg/L and oxalic acid of 45 mg/L. With effluents of Fenton‐like being controlled at pH 7.0, the pollutants could be coagulated further. The hydroxyl radicals measurement by means of electron paramagnetic resonance showed that Fenton‐like system could produce more HO· than did photo‐Fenton system. The total removal efficiencies of COD and color could reach 93.5 and 96.7%, respectively. © 2009 American Institute of Chemical Engineers Environ Prog, 2010