Abstract Sulfamethoxazole (SMX), a typical sulfonamide antibiotic, has been widely detected in secondary wastewater effluents and surface waters. In this work we investigated the oxidative degradation of SMX by commonly used oxidants of chlorine, ozone and permanganate. Chlorine and ozone were shown to be more effective for the removal of SMX (0.05–5.0mg/L), as compared with permanganate. Higher pH enhanced the oxidation of SMX by ozone and permanganate, but decreased the removal by chlorine. Moreover, the ozonation of SMX was significantly influenced by the presence of humic acid (HA), which exhibited negligible influence on the oxidation by chlorine and permanganate. Fairly lower mineralization of SMX occurred during the oxidation reactions, with the highest dissolved organic carbon (DOC) removal of 13% (for ozone). By using LC–MS/MS, 7, 5 and 5 oxidation products were identified for chlorine, ozone and permanganate and possible transformation pathways were proposed. It was shown that different oxidants shared some common pathways, such as the cleavage of SN bond, the hydroxylation of the benzene ring, etc. On the other hand, each of the oxidants also exhibited exclusive degradation mechanisms, leading to the formation of different transformation products (TPs). This work may provide useful information for the selection of oxidants in water treatment processes.