Purpose: To compare the performance in breast lesion characterization of one-view mediolateral (MLO) digital mammography plus digital breast tomosynthesis (DM-DBT) versus one-view craniocaudal (CC) DM-DBT versus two-view DM-DBT.Materials and methods: The institutional review board approved this retrospective study conducted on 138 women from the population of a previous prospective multicenter study, with 69 consecutive patients with benign or high-risk lesions and 69 randomized patients with breast cancer, all confirmed at pathology. Four radiologists (two senior and two junior) blinded to the clinical, mammographic and pathological data independently reviewed the MLO DM-DBT views, the CC DM-DBT views and the MLO + CC DM-DBT views using the American College of Radiology Breast Imaging-Reporting and Data System criteria for index lesion characterization. Areas under the receiver were calculated and compared for each reader and imaging protocol.Results: No significant differences in breast cancer characterization were observed between single MLO and CC views for all the readers. The added value of a second view was statistically significant for characterization in pooled data and for junior readers but not for senior readers (p ranging from 0.15 to 0.57 depending on the view and the senior reader). Finally, in 4 breast cancer cases, lesions were only detectable on the CC DM-DBT view in two cases and on the MLO DM-DBT view in the two other cases.Conclusion: Our results support the use of two-view DM-DBT for breast lesion characterization when the readers are inexperienced. There is no significant difference between CC and MLO views when diagnosis is performed with one view.