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Aims: Our purpose was to clarify the effect of sulfamethoxazole (SMX) on the start‐up period, particle formation, and treatment efficiency of an aerobic granular sludge system. Methods and Results: We compared an R1 granular sequencing batch reactor (GSBR) started with 5 μg L−1 SMX and an R2 GSBR started without SMX, as a control, to investigate the impact of a trace amount of SMX (5 μg L−1) on aerobic granular sludge (AGS) characteristics and the removal of conventional contaminants. AGS granulation in the R1 system was not inhibited by SMX, but the granule particle size was smaller than that in the R2 system. Both systems had good performance removing conventional pollutants. Extracellular polymeric substance secretion in the R1 system was lower than that in the R2 system. After stabilizing reactor operations, the SMX removal efficiency in the R1 system (~73.93%) was higher than that in the R2 system (~70.66%). The start‐up modes also determined the differences in the microbial community structure of the AGS systems. Conclusions: SMX‐activated AGS performed better than AGS without SMX. Significance and Impact of Study: The study can help engineers determine start‐up modes with varieties of antibiotics in AGS processes and provide references for the optimization of water treatment processes. [ABSTRACT FROM AUTHOR]