A reference field effect transistor (FET) fabrication method by using a perfluorosulfonated proton exchange membrane associated with ion-insensitive polymers is proposed. The single-layer film of the perfluorosulfonated polymer/photoresist composite among the eight films tested demonstrated the best performance of 5.8 mV/pH and 11.27 mV/pNa sensitivities. Meanwhile, the drift performances were 3.5 mV/h and less than 1 mV/h for the first and second 4 h tests. A high sensitivity of 52.1 mV/pH and a low interference of 4.61 mV/pNa were obtained in the range of pH 1-13 through the differential arrangement with ZrO2 gate ion-sensitive field-effect transistors (ISFETs). Meanwhile, the transconductance match of the proposed reference FET/ISFET pair would simplify the differential readout circuits.