To investigate the diagnostic performance of contrast-enhanced mammography (CEM) combined with the Kaiser score (KS) in digital breast tomosynthesis (DBT) BI-RADS 4A lesions to potentially reduce unnecessary breast biopsies.This retrospective study evaluated 106 patients with 109 DBT BI-RADS 4A lesions from June 2019 to June 2021. For the absence of enhancement on CEM, the lesions were downgraded to BI-RADS 3. For lesions with enhancement, the readers were asked to classify all enhancing lesions referring to the KS for breast MRI. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance. Two readers rated all cases and interreader agreement was assessed by Cohen's kappa coefficients.There were ninety-five benign lesions and 14 malignant lesions. CEM combined with KS's accuracy, represented by the area under the curve (AUC), ranged between 0.880 and 0.906. The use of the KS improved the performance, with a significant difference relative to a single BI-RADS reading or US (p < 0.001). CEM with KS had higher specificity than CEM with BI-RADS or US (p < 0.001), without difference in sensitivity (p > 0.05). CEM combined with KS could have potentially obviated 72 (75.8%) to 78 (82.1%) unnecessary benign biopsies in 95 benign lesions previously DBT classified as BI-RADS 4A. The interreader agreement was substantial (kappa: 0.727) for KS.CEM combined with KS may be used in DBT BI-RADS 4A lesions to substantially reduce unnecessary benign biopsies.• CEM combined with the Kaiser scoring system shows high diagnostic performance for DBT BI-RADS 4A lesions. • The application of CEM combined with the Kaiser scoring system may avoid 75.8% to 82.1% of unnecessary benign breast biopsies. • CEM combined with the KS aids clinical decision-making in DBT BI-RADS 4A lesions.© 2022. The Author(s), under exclusive licence to European Society of Radiology.