Inflammatory breast cancer is a rapidly growing, distinct form of locally advanced breast cancer that carries a guarded prognosis. To identify the genes that contribute to this aggressive phenotype, we compared under- and overexpressed sequences in an inflammatory breast tumor cell line with those of actively replicating normal human mammary epithelial cell lines using differential display. Of the 17 transcripts isolated and characterized from these experiments, overexpression of RhoC GTPase and loss of expression of a novel gene on 6q22, LIBC (lost in inflammatory breast cancer), were highly correlated (P<0.0095 and P<0.0013, respectively) with the inflammatory phenotype when a panel of archival inflammatory breast cancers was compared with noninflammatory stage III breast cancers by in situ hybridization. This study suggests two new molecular markers specific for inflammatory breast cancer.