Given the positive results of quercetin in in vitro genotoxicity studies, it is of interest to test the in vivo genotoxicity of this important dietary flavonoid, especially considering possible high intake by widely available supplements. In the present study quercetin was tested in a transcriptomic analysis for genotoxicity in liver and small intestine of mice. Quercetin (0.33%) supplemented to a high-fat diet was administered to mice during 12 weeks and compared with high-fat diet feeding. Serum ALT and AST levels revealed no indications for hepatotoxicity. General microarray pathway analysis of liver and small intestinal tissue samples showed no regulation of genotoxicity related pathways. In addition, analysis of DNA damage pathways in these samples, also did not point at genotoxicity. Furthermore, comparison with a published classifier set of transcripts for identifying genotoxic compounds did not reveal any similarities with the regulation of these classifier set of transcripts by quercetin, except for two of the transcripts which were regulated in opposite direction. Available microarray datasets of known genotoxic compounds, 2-acetylaminofluorene (2-AAF) and aflatoxin B1 (AFB1) in mice were taken along as positive controls for comparison, and indeed showed genotoxic properties (regulation of genotoxic related genes) in the analyses. This transcriptomic study showed that supplementation with quercetin at ~350 mg/kg bw/day for 12 weeks in mice gave no indications of quercetin-induced genotoxicity in liver and small intestine.