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Background Our aim was to compare the diagnostic performance of digital breast tomosynthesis (DBT)-galactography with that of full-field digital (FFD)-galactography for detecting intraductal breast lesions using an intra-individual design. Methods Forty-nine consecutive patients with spontaneous, unilateral, single-pore nipple discharge and inconclusive FFD mammography and ultrasonography underwent galactography with a “COMBO” technique combining FFD- and DBT-galactography acquisitions. Examinations were independently analysed by two breast radiologists with 10-year experience. Sensitivity, specificity, and accuracy for both FFD- and DBT-galactography were calculated having histological examinations of surgical specimens as a reference standard. Data were presented as percentages with their 95% confidence intervals (CI). McNemar test was used. Interobserver agreement was assessed by using Cohen κ test for both techniques. Results Sensitivity was 41/43 (95%, 95% CI 84.2–99.4) for DBT-galactography and 33/43 (77%, 95% CI 61.4–88.2) for FFD-galactography (p = 0.008), specificity 6/6 (100%, 95% CI 54.1–100.0) for both imaging tools, accuracy 47/49 (96%, 95% CI 86.0–99.5) and 39/49 (80%, 95% CI 65.7–89.8) (p = 0.038), respectively. The inter-observer agreement was 0.86 for DBT-galactography and 0.78 for FFD-galactography. The AGD resulted to 1.94 ± 0.64 for the combined technique. Conclusion DBT-galactography showed a significantly higher sensitivity and accuracy than FFD-galactography for the identification of the intraductal findings, improving the possibility of a reliable diagnosis in patients with pathologic nipple-discharge.