OBJECTIVES To compare quality of harvested tissue, false-negative rate, and complication rate of large-core needle breast biopsy (LCNBB) and directional, vacuum-assisted breast biopsy (DVABB) in non-palpable breast lesions. PATIENTS AND METHODS From 1994 to 1999, in 580 non-palpable breast lesions a stereotactically-guided breast biopsy was performed. 14-G LCNBB was used in 168 lesions (29 %). DVABB was used in 412 lesions (71 %; 11-G DVABB: 134 lesions 32.5 %, 14-G DVABB: 278 lesions 67.5 %). Following biopsy, patients underwent either surgical excision (n = 533; 93.8 %) or mammographical follow-up (n = 36; 6.2 %). Histological results of LCNBB, DVABB, surgical breast biopsy and follow-up results were compared and scored for their tissue quality on a three-point scale (1 = disagreement between biopsy and surgery; 2 = partial agreement; 3 = complete agreement). In addition, we determined the false negative and complication rate for both systems. RESULTS Histological examination after surgery and follow-up proved 262 (45.2 %) to be benign, 15 (2.6 %) to be high-risk lesions and 303 (52.5 %) to be malignant. In the tissue quality there was no significant difference between 14-G LCNBB (score = 2.94), 11-G DVABB (score = 2.92) and 14-G DVABB (score = 2.91) (p > 0.05). Particularly, in calcifications 11-G DVABB scored better (score = 2.92) than 14-G DVABB (score = 2.88) (p > 0.05). 14-G LCNBB had a lower false negative rate (1.8 %) than 11-G DVABB (3 %) and 14-G DVABB (3.2 %) (p > 0.05). There was no difference in the complication rate between the different needle types. CONCLUSIONS Our results indicate that both LCNBB and DVABB are reliable and safe techniques in the diagnosis of non-palpable breast lesions. However, the use of 14-G LCNBB seems to be advantageous in masses, the use of 11-G DVABB seems to be advantageous in asymmetric densities and calcifications.