The present study has aimed to quantify the role of pore blocking and cake layer in a laboratory scale hollow fibre membrane module in submerged configuration. The membrane reactor (MBR) was fed with raw wastewater, only screened with a 2-mm sieve, collected from the Palermo WWTP. The MBR was characterised by an operating volume of 190 L and equipped with an aeration system located on the bottom of the reactor. The MBR operated for 65 days. The permeate was extracted by imposing a constant flux through the membrane (21 Lh−1m−2). The results confirm the importance of pore blocking control during start-up. In particular, it provides a rapid irreversible fouling that takes place at the beginning of the filtration process, before the deposition mechanism. Therefore, low suspended solids concentration in the initial phase causes a fast irreversible fouling. This circumstance creates the need for more frequent chemical cleaning after start-up without inoculum. Finally, the results underline that the cake has a mainly reversible feature.