BackgroundContrast‐enhanced spectral mammography (CESM) with photon‐counting x‐ray detectors (PCDs) can be used to improve the classification of breast cancers as benign or malignant. Commercially‐available PCD‐based mammography systems use silicon‐based PCDs. Cadmium‐telluride (CdTe) PCDs may provide a practical advantage over silicon‐based PCDs because they can be implemented as large‐area detectors that are more easily adaptable to existing mammography systems.PurposeThe purpose of this work is to optimize CESM implemented with CdTe PCDs and to investigate the influence of the number of energy bins, electronic noise level, pixel size, and anode material on image quality.MethodsWe developed a Monte Carlo model of the energy‐bin‐dependent modulation transfer functions (MTFs) and noise power spectra, including spatioenergetic noise correlations. We validated model predictions using a CdTe PCD with analog charge summing for charge‐sharing suppression. Using the ideal‐observer detectability, we optimized CESM for the task of detecting a 7‐mm‐diameter iodine nodule embedded in a breast with 50% glandularity. We optimized the tube voltage, beam filtration, and the location of energy thresholds for 50 and 100‐μm pixels, tungsten and molybdenum anodes, and two electronic noise levels. One of the electronic noise levels was that of the experimental system; the other was half that of the experimental system. Optimization was performed for CdTe PCDs with two or three energy bins. We also estimated the impact of anatomic noise due to background parenchymal enhancement and computed the minimum detectable iodine area density in the presence of quantum and anatomic noise.ResultsModel predictions of the MTFs and noise power spectra agreed well with experiment. For optimized systems, adding a third energy bin increased quantum noise levels and reduced detectability by ∼55% compared to two‐bin approaches that simply suppress contrast between fibroglandular and adipose tissue. Decreasing the electronic noise standard deviation from 3.4 to 1.7 keV increased iodine detectability by ∼5% and ∼30% for two‐bin imaging and three‐bin imaging, respectively. After optimizing for tube voltage, beam filtration, and the location of energy thresholds, there was ∼a 3% difference in iodine detectability between molybdenum and tungsten anodes for two‐bin imaging, but for three‐bin imaging, molybdenum anodes provided up to 14% increase in detectability relative to tungsten anodes. Anatomic noise decreased iodine detectability by 15% to 40%, with greater impact for lower electronic noise settings and larger pixel sizes.ConclusionsFor CESM implemented with CdTe PCDs, (1) quantitatively‐accurate three‐material decompositions using three energy bins are associated with substantial increases in quantum noise relative to two‐energy‐bin approaches that simply suppress contrast between fibroglandular and adipose tissues; (2) tungsten and molybdenum anodes can provide nearly equal iodine detectability for two‐bin imaging, but molybdenum provides a modest detectability advantage for three‐bin imaging provided that all other technique parameters are optimized; (3) reducing pixel sizes from 100 to 50 μm can reduce detectability by up to 20% due to charge sharing; (4) anatomic noise due to background parenchymal enhancement is estimated to have a substantial impact on lesion visibility, reducing detectability by approximately 30%.