In this study, the major factors affecting sonolytic degradation of sulfamethazine (SMT), a typical pharmaceutically active compound, in water were evaluated. The factors tested included two operational parameters (i.e. initial SMT concentration and ultrasonic power), three dissolved gases (i.e. Ar, O2 and N2), five most frequently found anions in water (NO3(-),Cl(-),SO4(2-),HCO3(-)andBr(-)), ferrous ion (Fe(2+)), and four alcohols (methanol, ethanol, isopropyl alcohol, tert-butyl alcohol). Typically, the degradation rate was increased with the increasing initial SMT concentration and power. The degradation rate was accelerated in the presence of argon or oxygen, but inhibited by nitrogen. Effects of anions on the ultrasonic treatment were species-dependent. The SMT degradation rate was slightly inhibited by NO3(-),Cl(-),and,SO4(2-) but significantly improved by HCO3(-)andBr(-). The negative effects of alcohols acted as hydroxyl radicals scavengers with the following order: tert-butyl alcohol>isopropyl alcohol>ethanol>methanol. The synergetic effect of ferrous ion was mainly due to production of additional hydroxyl radicals (·OH) through Fenton chemistry. LC/MS/MS analysis indicated that the degradation of SMT by ultrasonic irradiation is mainly ascribed to ·OH oxidation. Of interest, although the SMT could be rapidly degraded by ultrasonic irradiation, the degradation products were rarely mineralized. For example, ~100% of 180 μM SMT was decomposed, but only 8.31% TOC was reduced, within 2h at an irradiation frequency of 800 kHz and a power of 100 W. However, the products became much biodegradable (BOD5/COD was increased from 0.04 to 0.45). Therefore, an aerobic biological treatment may be an appropriate post-treatment to further decompose the SMT degradation products.