Abstract Colorectal cancer (CRC) is the third most common cancer in both men and women worldwide, and the third leading cause of cancer death in the USA. Recent research suggests that oral microbiome may play important roles in the pathogenesis of colorectal cancer and other chronic diseases. We conducted a nested case-control study within the Southern Community Cohort Study to investigate the association of oral microbiome with subsequent risk of developing CRC. This study included 231 incident CRC cases and 462 controls individually matched on age, race, smoking, alcohol drinking, season-of-study enrollment and recruitment method, with ~74% subjects of African descent. The V4 region of 16S rRNA gene of the pre-diagnostic mouth rinse samples was deeply sequenced. Sequencing data were processed using QIIME and sequence reads were clustered into Operational Taxonomic Units (OTUs). In total, 11 phyla, 73 families and 134 genera were observed from study samples, and only 5 phyla, 12 families and 11 genera showed relative abundance >1%. Multiple bacteria taxa showed significant associations with CRC risk at P <0.05. Notably, within the phylum Firmicutes, four genera were associated with increased risk of CRC, including Peptococcus, Ruminococcaceae_ [G-1], Clostridiales_[F-1][G-1], and Mollicutes_[G-2], with ORs (95% CIs) being 1.34(1.11-1.63), 1.20(1.01-1.44), 1.44(1.07-1.92), and 2.24(1.38-3.63), respectively. Multiple taxa within other phyla were also associated with increased risk of CRC, such as the family Bifidobacteriaceae within phylum Actinobacteria with OR (95% CI) being 1.31(1.08-1.61), and genus Lautropia within phylum Proteobacteria with OR (95% CI) being 1.23(1.02-1.48), and phylum SR1 with OR (95% CI) being 1.27(1.07-1.52). We also found that the phylum Firmicutes and the species sp. Oral taxon 070, which belongs to the genus Streptococcus, were associated with decreased risk of CRC, with ORs (95% CIs) being 0.79(0.65-0.96) and 0.77(0.63-0.93), respectively. Most of these associations were observed among both African- and European- Americans. None of the associations remained significant after Bonferroni correction for multiple testing, which may be conservative. The tests were not independent because the higher-level taxa is an aggregate of lower-level taxa. In addition, most taxa showed low relative abundance and prevalence and we have low statistical power to investigate them. Conclusion: Our study suggested that multiple bacteria taxa may be associated with risk of CRC, and raised the possibility that the oral microbiome may play an important role in CRC etiology. Citation Format: Yaohua Yang, Qiuyin Cai, Xiao Ou Shu, William J Blot, Wei Zheng, Jirong Long. Prospective study of oral microbiome and colorectal cancer risk in low-income and African American populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4931. doi:10.1158/1538-7445.AM2017-4931