Reversible and irreversible fouling mechanisms for polyvinylidene fluoride (PVDF) hollow fiber membranes during constant flux microfiltration (MF) of secondary municipal wastewater effluent are reported. Infrared spectra of fouled membranes revealed a two-step mechanism for hydraulically irreversible surface deposition of foulants; initial binding of relatively hydrophobic molecules, which served as platform for further deposition of comparatively more hydrophilic molecules with progressive MF. Compressible cake filtration quantitatively described forward MF of the raw wastewater effluent. In contrast, analysis of fouling behavior after effluent organic matter (EfOM, measured as DOC) removal by different pretreatments revealed that the foulants deposited on the membrane surface are not the dominant reason for irreversible loss in permeability instead pointing to internal pore deposition as the main reason, which was verified by blocking law modeling over multiple filtration/backwashing cycles. Additionally, the extent of EfOM removal during pretreatment was not proportionally linked to consequent fouling, signifying the role of specific EfOM fractions in the feed water as being responsible for (ir)reversible fouling. Interestingly, MF of the raw wastewater effluent resulted in lower irreversible permeability loss when compared with pretreated wastewater, which was attributed to the cake layer serving as a dynamic membrane that reduced exposure of membrane pores to foulants.