Abstract Colitis-associated colorectal cancer (CAC) is one of clear examples of inflammation-carcinogenesis sequence, based on which strict control of colitis provides the right rationale of the intervention of anti-inflammatory drug on the chemoprevention. We have shown that 8-OHdG, which traditionally has been acknowledged as a marker of oxidative stress-related mutagenesis, could paradoxically exerted potent anti-inflammatory and anti-oxidant action in various inflammation models (Ock CY et al, Biochem Pharmacol, 2010). Based on the fact that Rac1 binds and activates STAT3 which is significantly up-regulated in inflammatory bowel disease (IBD) as well as CAC, we hypothesized that attenuation of Rac1-STAT pathway by exogenous 8-OHdG treatment may block inflammatory bouts in dextran sodium sulfate (DSS) induced colitis and can reduce carcinogenesis promoted by azoxymethane (AOM) followed by DSS ingestion. First we have checked whether exogenous 8-OHdG can ameliorate IBD, for which IL10 knock-out mice, IBD prone mice, are designed to ingest 5% DSS in tap water ad libitum for a week, and 8-OHdG (50, 100, or 150 mg/kg) is given intraperitoneal route daily. Treatment with 8-OHdG significantly reduced complication rates, pathologic grade of inflammation and edema compared with DSS only group. On pathogenic basis, the expressions of various inflammatory mediators such as TNF-α, IL-6, COX-2 and iNOS were decreased, as well as Rac1 activity and phosphorylation of STAT3 in 8-OHdG treated group in a dose-dependent manner. Next, in order to document the chemoprevention effects of 8-OHdG, mice were injected AOM (10 mg/kg) intraperitoneally followed by drinking 2.5% DSS for a week, after which AIN76 diet that contains 0.03 % and 0.06 % 8-OHdG was given for 20 weeks. As results, mice which consumed 8-OHdG-contained diet were significantly reduced tumor incidence and tumor multiplicity. Increased activity of Rac1 and phosphorylation of STAT3 with AOM plus DSS administration were significantly attenuated in 8-OHdG treatment group. These results were further validated with human colorectal adenocarcinoma cell line Caco-2 in vitro model. Conclusively, for the very first time, we clearly showed chemopreventive effect of exogenous 8-OHdG against CAC. Since 8-OHdG, one of well-known by-products generated by oxidative stress, paradoxically blocks inflammation-carcinogenesis sequence in colitis-associated cancer model, 8-OHdG could be a promising chemopreventive drug for the patient suffering from longstanding and extensive IBD, high risk group for CAC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 848. doi:10.1158/1538-7445.AM2011-848