A novel Fenton-like catalyst, metal organic framework MIL-100(Fe) with Fe/Fe mixed-valence coordinatively unsaturated iron center (CUS-MIL-100(Fe)), was synthesized, characterized, and used for the degradation of sulfamethazine (SMT). The catalytic performance of CUS-MIL-100(Fe) was investigated on the basis of various parameters, including initial pH, HO concentration, catalyst dosage, and initial SMT concentration. The results showed that CUS-MIL-100(Fe) could effectively degrade SMT, with almost 100% removal efficiency within 180 min (52.4% mineralization efficiency), under the reaction conditions of pH 4.0, 20 mg L SMT, 6 mM HO, and 0.5 g L catalyst. Moreover, CUS-MIL-100(Fe) displayed a higher catalytic activity than that of MIL-100(Fe) for SMT degradation. Combined with the physical-chemical characterization, the enhanced catalytic activity can be ascribed to the incorporation of Fe and Fe CUSs (coordinatively unsaturated metal sites), the large specific surface area, as well as the formation of mesopores. Furthermore, CUS-MIL-100(Fe) exhibited a good stability and reusability. The possible catalytic mechanism of CUS-MIL-100(Fe) was tentatively proposed.