We have developed a CMOS-based x-ray imaging detector in the same form factor of a standard film cassette (18 cm × 24 cm) for Small Field-of-view Digital Mammography (SFDM) applications. This SFDM cassette is based on our three-side buttable, 25 mm × 50 mm, 48μm active-pixel CMOS sensor modules and utilizes a 150μm columnar CsI(Tl) scintillator. For imaging up to 100 mm × 100 mm field-of-view, a number of CMOS sensor modules need to be tiled and electronically synchronized together. By using fiber-optic communication, acquired images from the SFDM cassette can be transferred, processed and displayed on a review station within approximately 5 seconds of exposure, greatly enhancing patient flow. We present the physical performance of this CMOS-based SFDM cassette, using established objective criteria such as the Modulation Transfer Function (MTF), Detective Quantum Efficiency (DQE), and more subjective criteria, by evaluating images from a phantom study and the clinical studies of our collaborators. Driven by the strong demand from the computer industry, CMOS technology is one of the lowest cost, and the most readily accessible technologies available for digital mammography today. Recent popular use of CMOS imagers in high-end consumer cameras have also resulted in significant advances in the imaging performance of CMOS sensors against rivaling CCD sensors. The SFDM cassette can be employed in various mammography applications, including spot imaging, stereotactic biopsy imaging, core biopsy and surgical biopsy specimen radiography. This study demonstrates that all the image quality requirements for demanding mammography applications can be addressed with CMOS technology.