Continuous drinking water exposure to hexavalent chromium [Cr(VI)] as sodium dichromate dihydrate (SDD) is linked to intestinal tumor development in mice but not rats. In this study, the dose-dependent gene expression effects of SDD (0.3-520mg/L) were evaluated in female Fischer rat and B6C3F1 mouse duodenal (Duo) and jejunal (Jej) epithelia following 7 and 90 days of drinking water exposure. Using HolomoGeneID, 13899 orthologs were identified as represented across the mouse and rat whole-genome 4x44K Agilent microarrays. At day 8, comparative analysis (|fold change|>1.5, P1(t)>0.999) identified 5013 differentially expressed mouse orthologs compared to 2790 rat orthologs in the Duo, with comparable numbers of orthologs (rat 3782, mouse 3334) in the Jej. Ortholog comparisons at day 91 suggest mouse Duo (3484) and Jej (3620) are ~2.5 times more responsive to Cr(VI) compared to rat Duo (1504) and Jej (1305). Automated dose-response modeling suggests the mouse had more orthologs exhibiting a sigmoidal dose-response compared to the rat, although the median EC50s were overall comparable (39-55 mg/L SDD). Functional annotation identified differentially expressed orthologs associated with oxidative stress, cell cycle, cell death and immune response, consistent with changes in GSH/GSSG levels, hyperplasia, apoptosis and inflammation. Several differentially expressed orthologs exhibited speciesspecific expression that was verified by QRT-PCR. For example, genes associated with inflammation (Ccl24: Émouse, Ñrat; C3: Érat, Ñmouse), transport (Scl25a25: Érat, Ñmouse) and growth (Areg: Émouse, Ñrat) exhibited divergent expression. Implications of these analyses for the mode of action for Cr(VI)-induced intestinal carcinogenesis will be discussed. Funded by the ACC Cr(VI) Panel.