In this study, a peracetic acid (PAA) alone process was systematically demonstrated to give a high efficiency in the selective degradation of sulfonamide antibiotics (SAs). The employment of scavengers and probe compounds in this process demonstrates the predominant role of PAA in direct oxidation, and the limited role of carbon-centered radicals (R-O • ) in the degradation of representative SA, sulfamethazine (SMT). The process also exhibits high tolerance towards solution pH and competing anions in wastewater, indicating its applicability in enhancing the biodegradation of SAs in wastewater. Furthermore, the relationships between the observed rate constants (k obs ) and the molecule descriptors for ten SA compounds are demonstrated through the assessment of structure-activity relationships, calculated from density functional theory (DFT). This study gives new insights into the selectivity, performance and mechanism of PAA direct-oxidation in SA degradation.