The long-term operation of two thermophilic anaerobic submerged membrane bioreactors (AnSMBRs) was studied using acidified and partially acidified synthetic wastewaters. In both reactors, cake formation was identified as the key factor governing critical flux. Even though cake formation was observed to be mostly reversible, particle deposition proceeds fast once the critical flux is exceeded. Very little irreversible fouling was observed during long-term operation, irrespective of the substrate. Critical flux values at the end of the reactors operation were 7 and 3 L/m2 h for the AnSMBRs fed with acidified and partially acidified wastewaters, respectively, at a gas superficial velocity of 70 m/h. Small particle size was identified as the responsible parameter for the low observed critical flux values. The degree of wastewater acidification significantly affected the physical properties of the sludge, determining the attainable flux. Based on the fluxes observed in this research, the membrane costs would be in the range of 0.5 €/m3 of treated wastewater. Gas sparging was ineffective in increasing the critical flux values. However, preliminary tests showed that cross-flow operation may be a feasible alternative to reduce particle deposition.