Simple SummaryScreening mammography reduces mortality from breast malignancy. However, breast cancer screening is, unfortunately, hindered due to the poor sensitivity of mammography in dense breasts: up to 15–30% of all cancers may be missed. Given the rapid development of Contrast-Enhanced Mammography (CEM) and its potential for diagnostic use, even in an asymptomatic population, it seems very important to correctly assess the Average Glandular Dose (AGD) for a single CEM examination. Few studies have compared the AGD of CEM versus Digital Mammography (DM) and protocols, including Digital Breast Tomosynthesis (DBT) plus DM, in the same group of patients. The additional role of tomosynthesis versus digital mammography in asymptomatic patients with dense breasts in screening examinations has been well investigated with encouraging results. In this study, we intend to compare the AGD and the diagnostic performance of CEM versus DM, and of CEM versus DM + DBT, performed in the same group of patients over the same period of time in a screening setting.AbstractThis study aims to evaluate the Average Glandular Dose (AGD) and diagnostic performance of CEM versus Digital Mammography (DM) as well as versus DM plus one-view Digital Breast Tomosynthesis (DBT), which were performed in the same patients at short intervals of time. A preventive screening examination in high-risk asymptomatic patients between 2020 and 2022 was performed with two-view Digital Mammography (DM) projections (Cranio Caudal and Medio Lateral) plus one Digital Breast Tomosynthesis (DBT) projection (mediolateral oblique, MLO) in a single session examination. For all patients in whom we found a suspicious lesion by using DM + DBT, we performed (within two weeks) a CEM examination. AGD and compression force were compared between the diagnostic methods. All lesions identified by DM + DBT were biopsied; then, we assessed whether lesions found by DBT were also highlighted by DM alone and/or by CEM. We enrolled 49 patients with 49 lesions in the study. The median AGD was lower for DM alone than for CEM (3.41 mGy vs. 4.24 mGy,p= 0.015). The AGD for CEM was significantly lower than for the DM plus one single projection DBT protocol (4.24 mGy vs. 5.55 mGy,p< 0.001). We did not find a statistically significant difference in the median compression force between the CEM and DM + DBT. DM + DBT allows the identification of one more invasive neoplasm one in situ lesion and two high-risk lesions, compared to DM alone. The CEM, compared to DM + DBT, failed to identify only one of the high-risk lesions. According to these results, CEM could be used in the screening of asymptomatic high-risk patients.