Degradation of sulfapyridine as a representative sulfonamide by the UV/chlorine process was investigated. Kinetic experiments revealed that aniline and sulfonamide moieties were sulfapyridine's main reaction sites with (OH)-O-center dot, and the aniline moiety was the preferable site for Cl-center dot attack. Effects of four influence factors (pH; humic acid, HA; HCO3-; Cl-) on the degradation kinetics were explored by response surface methodology, and it was found that pH and HA have the highest level influence (81%) among all influence variables (linear, quadratic, and interactive terms), and low pH and concentrations of HA were beneficial for degradation. Approximately 70% of sulfapyridine degradation was observed within 60 min in the UV/chlorine system (pH = 5) without HA. A kinetic model considering steady-state concentrations of reactive radicals and their second-order rate constants is suitable for predicting sulfapyridine degradation, elucidating that (OH)-O-center dot and Cl-center dot are major radicals for sulfapyridine degradation in freshwater, and (OH)-O-center dot and Cl-2(center dot-) are responsible for the degradation in coastal seawater.