A performance evaluation of small-area, high-spatial-resolution, active matrix flat-panel imager (AMFPI) prototypes, operated under mammographic conditions, is reported. These prototypes are based on two 512 x 512 pixel imagers employing novel designs to enhance signal performance for direct and indirect detection. The indirect detection prototype is based on a 75 μm pixel pitch array incorporating a continuous photodiode design, as opposed to the discrete photodiode design used in conventional flat-panel imagers. This array was coupled to a pair of commercially-available x-ray converters: (1) a 34 mg/cm2 Gd2O2S:Tb phosphor screen (Min-R, Kodak) and (2) a 150 μm thick structured CsI:Tl scintillator on a fiber-optic plate (FOS-HL, Hamamatsu). The direct detection prototype is based on a 100 μm pixel pitch array and uses a 240 μm thick, high gain mercuric iodide (HgI2) photoconductor. Measurements of sensitivity, MTF, NPS and DQE were performed with a 26 kVp mammography beam attenuated by a 4 cm BR-12 breast phantom at various radiation exposures. Results from empirical studies of sensitivity indicate that these imagers offer a substantial enhancement in signal over conventional flat-panel imagers. Measurements of DQE for the imagers show values greater than those obtained from high performance mammographic film-screen systems, under some conditions. These studies also show that the FOS-HL imager configuration despite its lower MTF, exhibits DQE performance (up to approximately 0.77) superior or equivalent to that of the Min-R configuration due to better optical properties of the converter. In addition, despite a smaller pixel pitch, both of these indirect detection configurations exhibit improved DQE in comparison to similar configurations employing a 97 μm pitch discrete photodiode design, especially at low exposures. Results of DQE measurements from the HgI2 photoconductor prototype are promising (DQE values up to approximately 0.6). Finally, calculations of potential DQE performance for hypothetical 50 μm pitch imagers, employing similar novel designs, were performed. These calculations were based on the cascaded systems formalism and used realistic inputs derived from empirical measurements. The results predict that the HgI2 configuration would provide high DQE performance (up to approximately 0.9), which would be largely unaffected by the magnitude of exposure, due to the high gain of the photoconductor. These calculations also indicate that the continuous photodiode configuration would provide high DQE (up to approximately 0.8), degraded only at low exposure by the effect of additive noise.