BACKGROUND: Sulfamethoxazole is found in surface and ground waters because it is usually not metabolized and simply passes through the human body after ingestion. This drug is difficult to degrade by conventional treatments and may cause environmental concerns. RESULTS: A rapid and efficient enzymatic degradation of sulfamethoxazole by a heme peroxidase, chloroperoxidase (CPO), was investigated in this work. The degradation efficiency of sulfamethoxazole reached 98.64% within 20 min at room temperature, atmospheric pressure and environment-friendly reaction conditions with an enzyme concentration of approximately 10(-9) mol L-1. High performance liquid chromatography-mass spectrometry analysis was employed to identify the intermediates and final products. Moreover, chemical oxygen demand (COD) measurements showed that pre-treatment by CPO-H2O2 oxidative degradation followed by existing bioremediation technologies can effectively improve the efficiency and thoroughness of decontaminating this drug from wastewater. The degradation efficiency was enhanced from 76.5% to 84.47%, and the COD removal increased from 29.72% to 51.32%. The eco-toxicity test using a green algae, Cinorella pyrenoidos, showed that the degraded products had lower toxicity than the parent drug. CONCLUSION: CPO catalyzed oxidative degradation is a promising alternative for treatment of wastewater containing sulfonamide drugs. This enzymatic method is also suitable for treatment of other sulfonamide antibiotics. (C) 2016 Society of Chemical Industry