An advanced oxidation process of combining cobalt and peracetic acid (Co/PAA) was developed to degrade sulfamethoxazole (SMX) in this study. The formed acetylperoxy radical (CH3CO3 •) through the activation of PAA by Co (Co2+) was the dominant radical responsible for SMX degradation, and acetoxyl radical (CH3CO2 •) might also have played a role. The efficient redox cycle of Co3+/Co2+ allows good removal efficiency of SMX even at quite low dosage of Co (<1 μM). The presence of H2O2 in the Co/PAA process has a negative effect on the degradation of SMX due to the competition for reactive radicals. The SMX degradation in the Co/PAA process is pH dependent, and the optimum reaction pH is near-neutral. Humic acid and HCO3 – can inhibit SMX degradation in the Co/PAA process, while the presence of Cl– plays a little role in the degradation of SMX in this system. Although transformation products of SMX in the Co/PAA system show higher acute toxicity, the low Co dose and SMX concentration in aquatic solution can efficiently weaken the acute toxicity. After reaction in the Co/PAA process, numerous carbon sources that could be provided for bacteria and algae growth can be produced, suggesting that the proposed Co/PAA process has good potential when combined with the biotreatment processes.