When treating wastewaters prone to inert precipitation with granular sludge systems, mineral formation needs to be properly addressed and controlled to ensure system’s long-term stability. In this work, an extensive study on mineral precipitation on the surface of anammox granular sludge is presented. A 7-L gas-lift reactor was inoculated with one-year stored biomass. A fast start-up procedure lead to volumetric load of up to 0,48 gN-NO2-/l/d, with a maximum specific nitrogen load of 0,28 gN-NO2-/gVSS/d and stable nitrite removal higher than 95%. Severe mineral precipitation was observed on the granules’ surface, after a few months of hard-water feeding and resulted in a dramatic deterioration of reactor performance. Substrate diffusion limitation from the bulk to the inner layers, insufficient mixing due to higher granule density and shear stress increase due to hard-particle collision were the main mechanisms that lead to progressive process disruption. Macroscopic evidences, SEM-EDX and ad hoc chemical analyses revealed that the inert formation was a calcite-like mineral. The criterion of gravimetric selection was applied to discard the highly dense granules affected by severe precipitation, which can be adopted for inert accumulation control in real-scale installations through waste sludge withdrawal from the bottom of up-flow reactors. The present study provides valuable knowledge for addressing operational problems due to intense inert formation in real-scale granular systems and for understanding the mechanisms behind related systems’ failures.