Semi-aromatic polyamide membranes have been widely commercialized and used in water treatment processes. Such membranes often have poor Ca2+ and Mg2+ rejection rates due to their intrinsic structural characteristics. Most approaches used to improve rejection are only focused on one kind of repulsion effect: lack of synergism. Thus, the enhancement of rejection is not remarkable. Herein, a novel monomer, trimesoyl-[4,4-dimethyl-5(4H)-azlactone] (TMDMA), was synthesized and used as a secondary reaction molecule in the interfacial reaction for simultaneously improving the steric hindrance and lowering the electrostatic attraction of semi-aromatic polyamide membranes. With the introduction of TMDMA, the mean effective pore size of the polyamide membrane is decreased from 0.23 nm to 0.18 nm. Moreover, the significantly decreased negative surface charge of the fabricated polyamide membrane is observed since the carboxyl from hydrolysis of the azlactone exhibits a higher pKa (acidity coefficient) than that of the benzoic acid. The desalination experiments reveal that the Ca2+ and Mg(2+ )rejection of the resulting membranes are increased by 26% (from 71.0% to 97%) and 14.0% (from 83% to 97%), respectively, while the water fluxes are maintained at 192 and 167 kg m(-2) h(-1) MPa-1, demonstrating a satisfactory water softening performance that exceeds commercial nanofiltration membranes. Additionally, the fabricated polyamide membranes can significantly resist the flux decline during fouling experiment that normally results from the deposition of Ca2+- foulant.