The purpose of this study is to compare the performance of a complementary metal–oxide–semiconductor (CMOS)-based digital x-ray imaging system with that of a charge-coupled device (CCD)-based system for small animal research. A CMOS-based digital x-ray imaging system was developed and tested. The core of this system is a detector module consisting of eight joint CMOS chips, each having a size of 512×1024 pixels with a readout unit on the side. The pixel size of the CMOS detectors is 0.048 mm. The contrast detail detectability of the CMOS-based system was studied using different phantoms, and compared with that of a CCD-based digital imaging system. The contrast detail curves of the CMOS-based image system, obtained from the observer-based studies, are highly comparable to the CCD-based imaging system, particularly at higher x-ray exposures. The images of fine structures of a mouse, acquired by the CMOS system, demonstrated the capability of the system in the studies of small animals. With integration potential, manufacturability, and low costs, the CMOS-based imaging systems could be used in animal studies and potentially become useful clinical tools for diagnosis.