Purpose: Inflammatory breast cancer (IBC) is associated with very poor prognosis. The aims of this study are (a) to prospectively identify differential gene expression patterns associated with IBC and (b) to confirm these pathways using tissue arrays. Experimental Design: For gene expression analysis, IBC (n = 14) was clinically defined as rapidonset cancer associated with erythema and skin changes, whereas non-IBC patients (n = 20) had stage III breast cancers, and cDNA analysis was carried out using theAffymetrix (Santa Clara, CA) HG-U133A microarrays. Tissue arrays were constructed from paraffin-embedded material, and the molecular phenotype of 75 IBC was compared with results from >2,000 non-IBC.Results: Gene expression analyses indicated that IBC has higher expression of genes associated with increased metabolic rate, lipid signaling, and cell turnover relative to non-IBC tumors. Consistent with the expression analysis, IBC had statistically higher Ki-67 (93 % versus 11%; P < 0.001). BAX expression, reflecting increased apoptosis and cell turnover, was significantly uniformly higher in almost all IBC (98% versus 66%; P < 0.05), whereas the expression of Bcl-2 was not significantly different. IBC tumors were more likely to be steroid hormone receptor negative (estrogen receptor, 49% versus 30%; P = 0.002; progesterone receptor, 68% versus 42%; P = 0.001). The expression of tyrosine kinases was not significantly different. E-cadherin was found to be expressed in 87% of IBC, whereas the expression p53 was not significantly different. Conclusion:This study is one of the largest molecular analyses of IBC. Both IBC and non-IBC are genetically heterogeneous with consistent differences in the molecular phenotype of IBC.Breast cancer is complex and heterogeneous, with a range of overlapping clinical phenotypes that manifest a wide variation in prognosis and outcome. Inflammatory breast cancer (IBC) is a rare form of invasive breast cancer characterized clinically by rapid onset of breast erythema, edema, and ridging, with the time from first symptom/sign to diagnosis of V3 months (1). Until the advent of systemic therapy, this disease was almost universally fatal. Approximately 20% of patients with IBC have gross distant metastases at the time of diagnosis (2), in contrast to <5% of invasive ductal carcinomas of no special type. The mean 5-year survival rate in most studies of patients with IBC with local therapy alone is <5%, with median survival from 12 to 36 months (3). This is in contrast to no-special-type breast cancer where the 5-year survival exceeds 50% with local treatment alone. Thus, with local therapy alone, the probability of surviving IBC is only one-tenth that of other invasive breast cancers. Hence, IBC provides an ideal clinical window to study the molecular events that contribute to metastases and poor survival outcome. However, little is known about the molecular biology of this unusual and lethal variant of invasive breast cancer. There has been limited research done on the genetic alte...