INTRODUCTION: The purpose of this study was to compare the diagnostic accuracy of dual-energy contrast-enhanced digital mammography (CEDM) as an adjunct to mammography (MX) +/- ultrasonography (US) with the diagnostic accuracy of MX +/- US alone. METHODS: One hundred ten consenting women with 148 breast lesions (84 malignant, 64 benign) underwent two-view dual-energy CEDM in addition to MX and US using a specially modified digital mammography system (Senographe DS, GE Healthcare). Reference standard was histology for 138 lesions and follow-up for 12 lesions. Six radiologists from 4 institutions interpreted the images using high-resolution softcopy workstations. Confidence of presence (5-point scale), probability of cancer (7-point scale), and BI-RADS scores were evaluated for each finding. Sensitivity, specificity and ROC curve areas were estimated for each reader and overall. Visibility of findings on MX +/- CEDM and MX +/- US was evaluated with a Likert scale. RESULTS: The average per-lesion sensitivity across all readers was significantly higher for MX +/- US +/- CEDM than for MX +/- US (0.78 vs. 0.71 using BIRADS, p = 0.006). All readers improved their clinical performance and the average area under the ROC curve was significantly superior for MX +/- US +/- CEDM than for MX +/- US ((0.87 vs 0.83, p = 0.045). Finding visibility was similar or better on MX +/- CEDM than MX +/- US in 80% of cases. CONCLUSIONS: Dual-energy contrast-enhanced digital mammography as an adjunct to MX +/- US improves diagnostic accuracy compared to MX +/- US alone. Addition of iodinated contrast agent to MX facilitates the visualization of breast lesions.