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RATIONALE AND OBJECTIVES To identify the outcomes of stereotactic vacuum-assisted large bore biopsies performed on sonographically-occult non-calcified mammographic lesions (NCL). MATERIALS AND METHODS In an IRB-approved retrospective study, we reviewed all NCL that underwent stereotactic biopsy from January 1, 2014 to December 31, 2017 at our institution, comparing patient age, lesion type, size and location with pathology outcome (benign, high-risk or malignant) using Wilcoxon-Mann-Whitney or Fisher's exact tests as appropriate. Multivariable logistic regression models were developed to decrease benign biopsies in our cohort with diagnostic performance assessed using receiver operating characteristic curve and area under the curve (AUC). RESULTS Of 222 biopsied lesions in 213 patients, 79.3% (176/222) were benign, 5.9% (13/222) malignant, and 14.9% (33/222) high-risk. NCL were less likely to be malignant compared to calcifications biopsied in the same period [5.9% vs 19.0% (243/1279), p < 0.001]. All 42 asymmetries and 33 architectural distortions were benign, while 8.7% (4/46) of masses and 8.9% (9/101) of focal asymmetries were malignant. Cancers were associated with older age (mean 65.2 vs 52.7 years, p < 0.001), smaller size (mean 9.5 mm vs 15.5 mm, p < 0.01), and concurrent breast cancer (p < 0.01) compared to benign/high-risk lesions. Multivariable logistic regression model using patient age >50 years, lesion type, and size <15 mm had a high diagnostic performance [AUC=0.89, 95%CI (0.83, 0.94)], and yielded the highest PPV [0.24; 95%CI (0.13, 0.38)], and highest number of avoided, unnecessary biopsies (172/209, 82%). CONCLUSION NCL biopsied under stereotactic guidance have low cancer yield (5.9%). A multivariate model integrating age, lesion size and type could potentially help avoid unwarranted biopsies in our cohort.