The purpose of this study was to assess whether general pathologists are able to make as accurate and reproducible a diagnosis on large-core needle biopsies as on open breast biopsy specimens. A total of 688 patients underwent a stereotactic large-core (14G) needle biopsy and subsequent surgical excision of 718 non-palpable breast lesions. Forty-two pathologists from 10 departments of pathology (generalists) made a diagnosis on both the needle and open biopsy specimens. Afterwards, three pathologists and two radiologists with extensive experience in breast pathology (experts) diagnosed all of the biopsy specimens. The general pathologists made a similar histological diagnosis as the experts in 632 (88%) of the needle biopsies and 649 (90%) of the open biopsy specimens. Accordingly, the interobserver agreement for the diagnosis of large-core needle biopsies between the general and experts pathologists was excellent (kappa 0.83) and not significantly different from the interobserver agreement for the diagnosis of open breast biopsies (kappa 0.86). However, many inconsistencies were observed in the category of borderline lesions: only 24% of the large-core needle biopsies and 43% of the open biopsies with an expert diagnosis of 'borderline' were diagnosed similarly by the general pathologists. Additionally, the risk of benign/malignant inconsistencies between general pathologists and experts was approximately 1 in 55 for both needle and open biopsies.