Fouling by the formation of a complex cake remains a major hindrance of membrane bioreactors. One approach to fouling mitigation is to add particles within the biofluid in order to improve sludge filterability. Despite a number of studies dealing with this topic, fouling mechanisms are still not clear. This study reports the use of an original methodology for better fouling understanding and mitigation. This original approach is based on in situ characterization of cake local structural properties together with a detailed fluid characterization using size exclusion chromatography and the monitoring of global filtration performances. In order to obtain comprehensive elements, the impact of particle addition within cakes having markedly different behaviours (slightly and highly compressible cake, different specific resistance) was investigated considering different biofluids and membranes. The results demonstrated that a potential beneficial effect of particles on filtration performance depended on the cake properties in the absence of particles. It was found that particle addition could only improve biofluid filterability when the fouling layer was highly compressible and consisted mainly of macromolecular protein. In addition, in situ characterization revealed that particles within the fouling layer strongly influenced organic matter deposition at the membrane. It also showed that the effect of particles on fouling mitigation depended on the environment surrounding them within the fouling layer.