The purpose of this study was to determine the accuracy of core needle biopsy (CNB) diagnosis of papillary breast lesions and to identify histologic features that can predict malignancy. We retrospectively reviewed 2876 CNB performed at MD Anderson Cancer Center (01/95-08/02) and identified 50 papillary lesions: 30 papillomas, eight atypical papillomas and 12 papillary carcinomas. Histopathological parameters were evaluated and radiographic findings were reviewed. When available, the CNB was compared with the excisional biopsy (EB) material. Carcinoma was confirmed by EB in 11/12 cases and invasion was correctly assessed in 67% of them. In EB, 6/8 (75%) atypical papillomas revealed carcinoma in situ or atypia and the remaining two (25%) were benign, six out of 30 (20%) papillomas had been excised and none had shown atypia; the remaining patients had clinical and radiological follow-up with no evidence of disease progression. We conclude that CNB is effective for assessing papillary breast lesions and that EB is more accurate in determining invasion. Cellular monotony, lack of myoepithelial cells, and cytologic atypia are more accurate predictors of malignancy (P<0.0001) than is the presence of mitoses (P<0.053). A diagnosis of carcinoma or atypical papilloma by CNB should warrant an EB, whereas benign papillomas may be followed if imaging findings are concordant.