Exposure to hexavalent chromium [Cr(VI)] in drinking water was previously reported to increase oral tumor incidence in F344 rats. To investigate the mode of action for these tumors, transcriptomic profiles in oral mucosa samples of F344 rats and B6C3F1 mice were analyzed following exposure to 0.1–180 ppm Cr(VI) for 7 or 90 days. In rats, genome-wide microarray analyses identified no significantly differentially expressed genes (DEGs) at either time point. In mice, 14 and 1 DEGs were respectively identified after 7 and 90 days of exposure. Therefore, relaxed statistical criteria were employed to identify potential DEGs (pDEGs), followed by high-throughput benchmark dose modeling to identify responsive pDEGs for pathway enrichment analysis. This identified 288 and 168 pDEGs in the rat oral mucosa, of which only 20 and 7 showed evidence of dose-response. No significant pathway enrichment was obtained with either pDEG or dose-responsive pDEG lists. Similar results were obtained in mice. These analyses indicate a negligible transcriptional response in the oral mucosa of both species. Comparison of the total number of gene changes in the oral mucosa of rats and mice with responses in the duodenum of animals from the same study demonstrated remarkable dose-response concordance across tissues and species as a function of tissue chromium concentration. The low chromium levels in the oral mucosa and negligible transcript response are consistent with an absence of tissue lesions. These findings are used to compare the merits of linear and nonlinear approaches for deriving toxicity criteria based on the oral tumors in rats. Environ. Mol. Mutagen. 57:706–716, 2016. © 2016 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc.