Although shale gas has become an important source of natural gas, it has problems associated with water pollution by producing high salinity wastewater (i.e. TDS>100,000mg/L). Membrane distillation (MD) can be applied to treat such wastewater but may suffer from fouling due to scale formation. Accordingly, this study focused on the use of antiscalants to retard scale formation in MD process for the treatment of high salinity wastewater. Experiments were performed using a laboratory-scale direct contact MD (DCMD) system. Seven different antiscalants were applied to the simplified synthetic wastewater. The results were analyzed using a simple theoretical model. It was found that the abilities to retard scale formation were different for different antiscalants. The difference in chemical structures of the antiscalants was attributed to the changes in their effect on scale prevention. Moreover, the mechanisms of flux decline seem to be different in the presence of antiscalants. Not only surface blockage but also internal pore blocking occurred during the MD operation, and the dominant fouling mechanism changed by the addition of the antiscalants.