The sensitivity to detect small breast cancers and the specificity of conventional mammography (CM) remain limited owing to an overlap in the appearances of lesions and surrounding structure. We propose to address the limitations accompanying CM using flat panel detector (FPD)-based cone beam CT breast imaging (CBCTBI). The purpose of the study is to determine optimal x-ray operation ranges for different sizes of normal breasts and corresponding glandular dose levels. The current CBCT prototype consists of a modified GE HighSpeed Advantage CT gantry, an x-ray tube, a Varian PaxScan 4030CB FPD, a CT table and a PC. Two uncompressed breast phantoms, with the diameters of 10.8 and 13.8 cm, consist of three inserts: a layer of silicone jell simulating a background structure, a lucite plate on which five simulated carcinomas are mounted, and a plate on which six calcifications are attached. With a single scan, 300 projections were acquired for all phantom scans. The optimal x-ray techniques for different phantom sizes were determined. The total mean glandular doses for different size phantoms were measured using a CT pencil ionization chamber. With the optimal x-ray techniques that result in the maximal dose efficiency for the different tissue thickness, the image quality with two different phantoms was evaluated. The results demonstrate that the CBCTBI can detect a few millimeter-size simulated carcinoma and ~ 0.2 mm calcification with clinically acceptable mean glandular doses for different size breasts.