Abstract Background To develop a predictive nomogram for breast cancer lympho-vascular invasion (LVI), based on digital breast tomography (DBT) data obtained from intra- and peri-tumoral regions. Methods One hundred ninety-two breast cancer patients were enrolled in this retrospective study from 2 institutions, in which Institution 1 served as the basis for training (n = 113) and testing (n = 49) sets, while Institution 2 served as the external validation set (n = 30). Tumor regions of interest (ROI) were manually-delineated on DBT images, in which peri-tumoral ROI was defined as 1 mm around intra-tumoral ROI. Radiomics features were extracted, and logistic regression was used to construct intra-, peri-, and intra- + peri-tumoral radiomics models. Patient clinical data was analyzed by both uni- and multi-variable logistic regression analyses to identify independent risk factors for the non-radiomics clinical imaging model, and the combination of both the most optimal radiomics and clinical imaging models comprised the comprehensive model. The best-performing model out of the 3 types (radiomics, clinical imaging, comprehensive) was identified using receiver operating characteristic (ROC) curve analysis, and used to construct the predictive nomogram. Results The most optimal radiomics model was the intra- + peri-tumoral model, and 3 independent risk factors for LVI, maximum tumor diameter (odds ratio [OR] = 1.486, 95% confidence interval [CI] = 1.082–2.041, P = 0.014), suspicious malignant calcification (OR = 2.898, 95% CI = 1.232 ~ 6.815, P = 0.015), and axillary lymph node (ALN) metastasis (OR = 3.615, 95% CI = 1.642–7.962, P