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AbstractA computational model was developed to investigate the significance of system design and operating conditions on the rejection of neutral, low‐MW organics by reverse osmosis for potable reuse. The model demonstrated that the decrease in local rejection as net driving pressure decreases is substantially greater for moderately rejected compounds than for highly rejected compounds. At recovery values less than 70%, the local permeate concentration can exceed the pressure vessel feed concentration for moderately rejected compounds. System‐level rejection of moderately rejected compounds is likewise substantially more sensitive to operating conditions than highly rejected compounds. The findings highlight a drawback of relying on rejection results from bench‐scale testing that operates at low recovery, which invariably has higher rejection than full‐scale systems operating at similar pressure. The analysis demonstrates a trade‐off in which the low‐pressure, high‐recovery operation desired for potable reuse systems can be detrimental to the removal of low‐MW neutral organics. The removal of low‐MW neutral organics can be improved if organics rejection is explicitly evaluated during the design process.