Occurrence and effects of antibiotics and antibiotic resistance in various wastewater treatment systems have been widely investigated. However, few reports address the impacts of antibiotic exposure on wastewater treatment system operating characteristics, especially the characteristics of sludge granules under long-term operation. In this study, two laboratory scale anoxic-aerobic systems were established to investigate the combined effects of tetracycline and sulfamethoxazole. The results indicated that under long-term exposure to 5 mg·L-1 tetracycline and 1 mg·L-1 sulfamethoxazole, removals of chemical oxygen demand and total nitrogen were inhibited, the tendency of sludge bulking was increased, more filamentous bacteria were observed and more extracellular polymeric substance was secreted. This tendency was stronger than that from exposure to tetracycline alone. Molecular biological analysis indicated that the microbial community changed significantly especially with Thiothrix (instead of Sphaerotilus under tetracycline alone) becoming the dominant population under combined antibiotics. The results are relevant for operation of WTS receiving wastewater with high antibiotic concentrations.