The long-term performance of forward osmosis during simulated wastewater reclamation was investigated for 120 h operation with a focus upon the influence of flux on flux decline and the synergistic effect of fouling on concentration polarization. Our comprehensive investigation focused on different fluxes (25; 30; 34 LMH) for simulated wastewater containing either a high protein or a low protein fraction. Compared to an initial flux of 25 LMH, operation at an initial 34 LMH favored the formation of a thicker and more compact cake layer which resulted in significant increase in both cake structural parameter (four-fold) and cake layer enhanced concentration polarization (ten-fold). After 40 h operation without physical cleaning the additional effect of cake layer enhanced concentration polarization and fouling resistance consumed 25% of the total driving force; the significant internal concentration polarization still had the greatest impact. In contrast operation at the lower flux of 25 LMH generated less fouling with a lower cake structural parameter (119 μm). The resultant flux decline was only 3% in contrast to the 15–18% found for the higher flux of 34 LMH. For operation above an initial 30 LMH it was found that FO fouling became irreversible if the wastewater contained a high protein fraction. Overall for a thin film composite membrane and a wastewater with a foulant concentration of 160 mg/L an initial flux of 25 LMH is the recommended threshold; this is 25% less that the critical value determined in earlier short-term studies.