Contrast-medium-enhanced digital mammography (CEDM) is an image subtraction technique which might help unmasking lesions embedded in very dense breasts. Previous works have stated the feasibility of CEDM and the imperative need of radiological optimization. This work presents an extension of a former analytical formalism to predict contrast-to-noise ratio (CNR) in subtracted mammograms. The goal is to optimize radiological parameters available in a clinical mammographic unit (x-ray tube anode/filter combination, voltage, and loading) by maximizing CNR and minimizing total mean glandular dose , simulating the experimental application of an iodine-based contrast medium and the image subtraction under dual-energy nontemporal, and single- or dual-energy temporal modalities. Total breast-entrance air kerma is limited to a fixed (1 R, similar to screening studies). Mathematical expressions obtained from the formalism are evaluated using computed mammographic x-ray spectra attenuated by an adipose/glandular breast containing an elongated structure filled with an iodinated solution in various concentrations. A systematic study of contrast, its associated variance, and CNR for different spectral combinations is performed, concluding in the proposal of optimum x-ray spectra. The linearity between contrast in subtracted images and iodine mass thickness is proven, including the determination of iodine visualization limits based on Rose's detection criterion. Finally, total breast-entrance air kerma is distributed between both images in various proportions in order to maximize the figure of merit . Predicted results indicate the advantage of temporal subtraction (either single- or dual-energy modalities) with optimum parameters corresponding to high-voltage, strongly hardened spectra. For temporal techniques, CNR was found to depend mostly on the energy of the iodinated image, and thus reduction in could be achieved if the spectral energy of the noniodinated image is decreased and the breast-entrance air kerma is evenly distributed between both acquisitions. Predicted limits, in terms of iodine concentration, are found to guarantee the visualization of common clinical angiogenic concentrations in the breast.