Columnar cell lesions of the breast are detected with increasing frequency in routine pathology practice, in part as a result of the widespread biopsy of nonpalpable breast abnormalities detected by screening mammography. Immunohistochemical investigation of the lesions in relation to the normal breast or to other breast pathologies is not well characterized, and the malignant potential of this spectrum of lesions has not been examined clinically. In this study, a cohort of 45 breast specimens containing columnar cell lesions, in particular, columnar alteration of lobules with prominent apical snouts and secretions (CAPSS), was investigated for expression of a series of breast tumor biomarkers. Using a semiquantitative immunohistochemical scoring system, up-regulation of estrogen, progesterone, and androgen receptors in CAPSS lesions to levels not significantly different from that in in situ or invasive breast tumors was identified. In four cases where CAPSS within a specimen lacked expression of a steroid hormone receptor, the coexisting in situ or invasive carcinoma also lacked expression of that receptor. In 81% of CAPSS lesions, E-cadherin immunostaining was reduced in isolated foci of cells or was decreased in intensity in all cells within the lesion. Quantitation of Ki-67 immunostaining demonstrated that proliferation of cells within CAPSS lesions was increased, compared with normal breast epithelium, but was lower than that detected in in situ or invasive cancers within the same specimens. Results of these analyses indicate that CAPSS shares immunophenotypic alterations with other premalignant lesions, the clinical implications of which may be investigated using established breast tumor biomarkers.