In this study, a modified Fenton system using calcium peroxide (CaO2) powder, as an effective source of hydrogen peroxide (H2O2), for the degradation of sulfamethoxazole (SMX) in aqueous solution was investigated. Our results indicated that degradation of SMX in Fe(II)-EDTA catalyzed CaO2 system was readily more efficient than in Fe(II) catalyzed CaO2 system. The SMX degradation efficiency was found maximum at pH 6.0 and SMX degradation was suppressed as the initial solution pH was increased. Nevertheless overall removal efficiency in this system was favorable near to neutral pH. In addition, it was observed that the higher bicarbonates (HCO3-) contents had a considerable scavenging ability to SMX degradation while low concentration exhibited auspicious role. The presence of chlorides (Cl-), nitrates (NO3-), sulfates (SO42-), and humic acid (HA) could improve SMX removal in this Fenton-like system. Furthermore, chemical probe and radical scavenging activity confirmed the formation of hydroxyl (HO center dot) and superoxide (O-2(-)center dot) radicals, and also described that the SMX degradation was predominantly due to the HO center dot-induced oxidative destruction. Electron paramagnetic resonance (EPR) studies for different systems, different pH values and different reaction times were carried out to determine the HO center dot radical intensities. EPR results showed that HO center dot intensities were higher in Fe(II)-EDTA catalyzed CaO2 system, at pH 6.0 and at 90 s reaction time, respectively. Intermediate products of SMX were identified and possible mechanism of SMX degradation was suggested. In conclusion, this work provided comprehensive knowledge for the use of Fe(II)-EDTA catalyzed CaO2 system for remediation of SMX contaminated sites.