A full-scale anaerobic side-stream reactor (ASSR) for sludge reduction was monitored in terms of sludge production and compared with the previous conventional activated sludge configuration (CAS). A detailed solid mass balance was calculated on the whole full-scale plant to estimate the sludge reduction associated with the ASSR. The activity of the biomass, which undergoes alternation of aerobic and anaerobic conditions, was investigated by the respirometric test. The ASSR promoted a reduction of heterotrophic biomass activity and the substrate consumption rate in the activated sludge implemented with ASSR (AS + ASSR) was 36% smaller than in the CAS period. The solid mass balance indicated a sludge reduction of 28%. During the 270-day operation, the observed sludge yield passed from 0.438 kgTSS/kgCOD in the CAS to 0.315 in the AS + ASSR configuration. The solubilization of chemical oxygen demand (COD), NH4 +-N and orthophosphate were verified under anaerobic conditions. The results suggest that the possible mechanisms of sludge reduction were the increase of the system sludge retention time (SRT) by ASSR addition, and the reduction in heterotrophic biomass activity added to the organic compounds' hydrolysis.