Sustainable wastewater management strategies are required to further minimize impacts of high-volume hydraulic fracturing (HVHF) as current practices such as reuse or direct disposal have long term limitations. Membranes can provide superior effluent quality in HVHF wastewater treatment, but the application of these systems is severely limited by membrane fouling. However, the key fouling components in HVHF wastewater have not yet been clearly identified and characterized. Here we demonstrate that fouling of microfiltration membranes by synthetic flowback water is mostly due to polyacrylamide (PAM), a major additive in slickwater fracturing fluids. A synthetic fracturing fluid was incubated with Marcellus Shale under HVHF conditions (80 ℃, 83 bar, 24 h) to generate synthetic flowback water. Different HVHF conditions and fracturing fluid compositions generated a fouling index for flowback water ranging from 0.1 to 2000 m−1, with these values well correlated with the peak molecular weight (MW) (ranging from 10 to 1.5 × 104 kDa) and the concentration of high MW components in the water. The lowest fouling index was observed when PAM was further degraded by ammonium persulfate under HVHF conditions, although this is infrequently used with PAM in current fracturing operations. These results highlight the importance of PAM and its degradation products in fouling of subsequent membrane systems, providing insights that can help in the development of effective treatment processes for HVHF wastewater.