Melamine is recalcitrant and toxic to bacteria in conventional activated sludge systems. In this study, we investigated the degradation and toxicity of melamine in a membrane bioreactor (MBR) system operated at high activated sludge concentrations (∼8.5 g TSS/L). Melamine was dosed at 3 mg/L for about 100 days. The average melamine removal efficiency in the MBR system was 20 ± 11%. Meanwhile, batch studies showed the acclimated sludge from the MBR had higher removal efficiencies after the depletion of readily biodegradable substrate (acetate) while non-acclimated sludge did not remove any melamine. As acclimated sludge had removal efficiencies ranging from 33 ± 6% (by 1.7 g TSS/L biomass) to 41 ± 10% (by 8.5 g TSS/L biomass), microbial specialists with unique hydrolytic enzymes in the acclimated sludge were likely responsible for melamine degradation. Since bacteria prefer to use readily biodegradable substrates for growth in the MBR, the population of microbial specialists capable of degrading melamine or the capability of cometabolism appeared not to increase with an increase in biomass concentration. Nevertheless, because of high sludge concentrations and thus low mass ratio of toxic melamine to biomass in the MBR, the long-term melamine exposure did not affect MBR activated sludge performance.