In order to fabricate nanofiltration (NF) membranes with high flux and anti-fouling properties, polyethylene glycol-functionalized polyhedral oligomeric silsesquioxane (PEG-POSS) nanoparticles were incorporated into the polyamide membrane during the interfacial polymerization of piperazine (PIP) and trimesoyl chloride (TMC) on polyethersulfone ultrafiltration substrate. The hydrophilicity, surface smoothness and electronegativity of the hybrid membrane were increased compared with the pristine polyamide membrane. The optimal preparation condition determined according to desalination performance was as follows, PEG-POSS content of 0.5% (w/v), PIP and TMC concentration of 0.1% (w/v) and reaction time of 2 min. The PEG-POSS nanoparticles constructed water channels networks and increased free volume of polyamide layer, contributing to the enhanced water permeation of hybrid membrane. The highest pure water flux of 38.7 L m(-2) h(-1) at 0.2 MPa which was nearly twice that of pristine polyamide membrane was achieved without reducing the salt rejection of Na2SO4 (87.1-91.6%). Meanwhile, the as-fabricated membranes exhibited exceptional anti-fouling performance. The flux recovery ratio (FRR) of the hybrid membrane reached up to 97.0%, 98.4% and 94.5% using bovine serum albumin, humid acid and sodium alginate as model foulants.