OBJECTIVE: To assess the diagnostic accuracy of Dual-Energy Contrast-Enhanced Digital Mammography (CEDM) as an adjunct to mammography (MX) versus MX alone and versus mammography plus ultrasound (US). MATERIALS AND METHODS: 120 women with 142 suspect findings on MX and/or US underwent CEDM. A pair of low- and high-energy images was acquired using a modified full-field digital mammography system. Exposures were taken in MLO at 2 min and in CC at 4 min after the injection of 1.5 ml/kg of an iodinated contrast agent. One reader evaluated MX, US and CEDM images during 2 sessions 1 month apart. Sensitivity, specificity, and area under the ROC curve were estimated. RESULTS: The results from pathology and follow-up identified 62 benign and 80 malignant lesions. Areas under the ROC curves were significantly superior for MX+CEDM than it was for MX alone and for MX+US using BI-RADS. Sensitivity was higher for MX+CEDM than it was for MX (93% vs. 78%; p < 0.001) with no loss in specificity. The lesion size was closer to the histological size for CEDM. All 23 multifocal lesions were correctly detected by MX+CEDM vs. 16 and 15 lesions by MX and US respectively. CONCLUSION: Initial clinical results show that CEDM has better diagnostic accuracy than mammography alone and mammography+ultrasound.