Background Contrast-enhanced mammography (CEM) is an emerging modality that generates low-energy (LE) images that are visually equivalent to full-field digital mammography (FFDM) and recombined images that show lesion vascularity such as MRI. Supplemental whole-breast US increases cancer detection rates when performed with FFDM but not with MRI. Purpose To compare the performance of CEM, LE images, and LE images supplemented with whole-breast US in breast cancer detection during screening. Materials and Methods This prospective study recruited female participants from December 2014 to February 2019 who were scheduled for screening mammography and whole-breast US. CEM (including LE images and recombined images) and whole-breast US images were interpreted by separate breast radiologists blinded to the findings on images from the other modality. Statistical differences in sensitivity and specificity, positive predictive value (PPV), negative predictive value, and abnormal interpretation rate were assessed. Biopsy recommendation rate and PPVs of biopsies performed (PPV