A protein concentration measurement system with two-port flexural plate-wave (FPW) biosensors using a frequency-shift readout technique is presented in this paper. The proposed frequency-shift readout method employs a peak detecting scheme to measure the amount of resonant frequency shift. The proposed system is composed of a linear frequency generator, a pair of peak detectors, two registers, and a subtractor. The frequency sweep range of the linear frequency generator is limited to 2 MHz to 10 MHz according to the characteristics of the FPW biosensors. The proposed frequency-shift readout circuit is carried out on silicon using a standard 0.18 μm CMOS technology. The sensitivity of the peak detectors is measured to be 10 mV. The power consumption of the proposed protein concentration measurement system is 48 mW given a 0.1 MHz system clock.