Edema toxin (EdTx), which is a combination of edema factor and a binding moiety (protective antigen), is produced by Bacillus anthracis, the etiological agent of anthrax. EdTx is an adenylyl cyclase enzyme that converts adenosine triphosphate to adenosine-3',5'-monophosphate, resulting in interstitial edema seen in anthrax patients. We used GeneChip analysis to examine global transcriptional profiles of EdTx-treated RAW 264.7 murine macrophage-like cells and identified 71 and 259 genes whose expression was significantly altered by the toxin at 3 and 6h, respectively. Alteration in the expression levels of selected genes was confirmed by real time-reverse transcriptase polymerase chain reaction. The genes with up-regulated expression in macrophages in response to EdTx-treatment were known to be involved in inflammatory responses, regulation of apoptosis, adhesion, immune cell activation, and transcription regulation. Additionally, GeneChip analysis results implied that EdTx-induced activation of activator protein-1 (AP-1) and CAAAT/enhancer-binding protein-beta (C/EBP-beta). Gel shift assays were therefore performed, and an increase in the activities of both of these transcription factors was observed within 30 min. EdTx also inhibited tumor necrosis factor alpha production and crippled the phagocytic ability of the macrophages. This is the first report detailing the host cell global transcriptional responses to EdTx.