Background: When cells fail to maintain a balance between proliferation, terminal differentiation, and programmed cell death, cancer often results. The CCAAT/enhancer-binding protein (C/EBP) family of transcription factors regulates many genes involved in the processes of proliferation and terminal differentiation. The messenger RNA for C/EBPβ is translated into two major isoforms, LAP (liverenriched activating protein) and LIP (liver-enriched inhibitory protein). LIP levels appear to be elevated in mouse mammary tumors but not in hyperplastic mammary tissues. We tested whether LIP expression is elevated in human breast cancer and whether elevated expression is associated with biologic predictors of the aggressiveness of the disease. Methods: Homogenates of infiltrating ductal carcinoma specimens from 39 women were analyzed for C/EBPβ protein content by western blot analysis, and the ratio of LAP to LIP in specimens containing high levels of LIP (i.e., levels approximately 15 times higher than those in tumor specimens that express little or no LIP) was also determined. Nonparametric statistical analyses were performed. Results: LIP was present at high levels in nine of 39 specimens of infiltrating ductal carcinoma. Eight of the nine specimens of infiltrating ductal carcinoma that contained high levels of LIP were negative for estrogen receptor and progesterone receptor (ER ⁻ /PR ⁻ ); all nine tumors were aneuploid and poorly differentiated, and eight of nine were highly proliferative. Of the tumors that contained LIP at low or nondetectable levels, six of 30 were ER ⁻ /PR- ⁻ , 17 of 29 were aneuploid, eight of 27 were highly proliferative, and 11 of 30 were poorly differentiated. Implication: LIP expression should be evaluated further as a prognostic marker for patients with breast cancer.