In this paper, we design a signal processing circuit for quartz crystal microbalance (QCM) biosensors. The proposed signal processing circuit, which consists of two oscillators, a mixer, a low-pass filter, can be used to measure small amount of QCM biosensors' frequency variation at a fundamental resonance frequency. Based on the principle of heterodyne technique, the QCM biosensors' frequency variation can be converted into the low frequency composition by a second-order low-pass filter. The output of the low-pass filter is digitized to a stream of digital pulses by a simple digital buffer which represents the corresponding QCM biosensor's frequency variation. The proposed signal processing circuit is implemented by 0.35-μm CMOS technology, and the chip layout area is 1060 mm 2. In the proposed circuit, the maximum range of the detectable frequency variation is 26 kHz under the resolution of 0.5 Hz. In system verification, the proposed signal processing circuit chip is successfully applied in the signal processing of α-Amylase QCM biosensors to detect the change of low concentration biomolecular.