Background: Recent studies suggest that the poorer breast cancer outcome observed in African-American women (AAW) may, in part, result from underlying molecular factors. The purpose of this study was to investigate gene expression differences between Caucasian-American women (CAW) and AAW that may contribute to this poorer prognosis. Methods: The expression of 84 genes involved in breast carcinoma prognosis, response to therapy, estrogen signaling, and tumor aggressiveness was assessed in age- and stage-matched CAW and AAW paraffin-embedded breast cancer specimens. The Wilcoxon-Mann-Whitney Test was used to identify genes with a significant difference in expression between CAW and AAW. To determine if the differentially expressed genes could segregate between the CAW and AAW, we performed semi-supervised principal component analysis (SSPCA). Results: Twenty genes were differentially expressed between AAW and CAW. SSPCA incorporating these 20 genes segregated AAW and CAW into two distinct groups. AAW were significantly (p<0.05) more likely to display aberrations in G1/S cell-cycle regulatory genes, decreased expression of cell-adhesion genes, and low to no expression of ESR1, PGR, ERBB2 and estrogen pathway targets. Conclusions: The gene expression differences identified between AAW and CAW may contribute to more aggressive disease, resistance to therapy, enhanced metastatic potential and poor clinical outcome. These findings support the hypothesis that breast cancer specimens collected from AAW display distinct gene expression differences compared to similar tissues obtained from CAW. Additional population-based studies are necessary to determine if these gene expression variations contribute to the highly aggressive and treatment-resistant breast cancer phenotype frequently observed in AAW. © 2012 Grunda et al.; licensee BioMed Central Ltd.