PURPOSE: The purpose of this study was to assess the value of adding digital breast tomosynthesis (DBT) to full-field digital mammography (FFDM) in the diagnostic workup of breast cancer and to determine which lesion variables affect cancer detectability in the combined modality. METHODS: Between March and May 2012, paired FFDM and DBT images were obtained from 203 women as part of a diagnostic workup for breast cancer. Images from FFDM alone, DBT alone, and DBT combined with FFDM were reviewed in separate sessions by six blinded readers. Jackknife alternative free-response receiver operating characteristic (JAFROC) figure of merit (FOM), sensitivity, and specificity were compared between the modalities. Lesion characteristics affecting the cancer detection rate when using the combined modality were also analyzed. RESULTS: Among the 203 women, 126 women had a total of 129 malignancies and 77 women had total of 77 benign lesions. The overall JAFROC FOM of the combined modality was higher than that of FFDM alone (0.827 vs. 0.775, p<0.001) and that of DBT alone was higher than that of FFDM alone (0.807 vs. 0.775, p=0.027). The overall sensitivity of the combined modality was higher than that of FFDM alone (80.0% vs. 73.2%, p<0.001) and that of DBT alone was higher than that of FFDM alone (78.3% vs. 73.2%, p=0.007). Compared to FFDM alone, the combined modality detected an additional 48 cancers. Using the combined modality, the presence of masses or microcalcifications was significantly associated with the cancer detection rate (p<0.001). CONCLUSION: The combination of DBT with FFDM results in a higher diagnostic yield than FFDM alone. Additionally, DBT alone performs better than FFDM alone. However, even when DBT is combined with FFDM, breast cancers with no discernible masses and those lacking calcifications are difficult to detect.