Oxic-settling-anaerobic (OSA) process is effective in minimizing sludge production, by inserting an anaerobic side-stream reactor (ASSR) in the recycling bypass. Interchange ratio (IR), the quantity ratio of sludge entering the ASSR to the sludge in the main stream reactors, is one of the most important parameters for OSA process. In the present study, a laboratory-scale anaerobic/anoxic/oxic (A2/O) process combined with an ASSR (A2/O-ASSR) was operated for 366 days in parallel with a conventional A2/O process to investigate the effects of IR on sludge reduction. IR was assigned values of 5%, 8%, 10%, and 15%, and the A2/O-ASSR process achieved 14.0%, 16.0%, 24.1%, and 13.7% of sludge reduction, respectively. At the optimum IR of 10%, high through-put sequencing analysis showed that the microbes responsible for pollutant removal and ubiquitous in wastewater treatment remained predominant in the two systems, and slow-growing microbes related to hydrolysis, nitrogen and phosphorus removal increased in the A2/O-ASSR process, which probably played a key role in sludge reduction. 40.6-58.6% of sludge reduction was caused by sludge decay in the ASSR. The tiny amount of extracellular polymeric substance released in the A2/O-ASSR process was subthreshold to cause remarkable sludge reduction.