Background: The presence of certain bacteria among or adjacent to tumor cells may contribute to colorectal cancer (CRC) development. However, the effect of the tumor microbiome on survival in CRC patients undergoing treatment is poorly understood. We hypothesize that intra-tumoral microbes correlate with overall survival (OS) in CRC patients. Methods: We obtained RNA-seq data from CRC tumor biopsies from patients treated at The Ohio State University Comprehensive Cancer Center as part of the Oncology Research Information Exchange Network (ORIEN). Reads were aligned to human and exogenous genomes using TopHat2 and Kraken2/Bracken, respectively. Results: The analyzed cohort included 99 CRC patients with an age range from 31-83 years, 62% female, and 44% with metastatic CRC. Therapies received prior to sample collection were grouped into chemotherapy with or without radiation (37%), antiVEGF/EGFR therapies (33%), no systemic therapy (23%), immunotherapy (3%); 3% were unknown. Overall, eleven bacteria were significantly associated with shorter OS, including a species in the genus Clostridium and Vibrio. Conversely, five other bacteria including several commensal gut microbes, were associated with longer OS. In patients who received chemotherapy with or without radiation (n = 38), several microbes were significantly associated with shorter OS, including a member of the genus Streptomyces. Only three bacteria were significantly associated with longer OS. In the patients who received antiVEGF/EGFR therapies (bevacizumab, cetuximab, panitumumab) (n = 33), several bacterial taxa were associated with shorter OS. In addition, bacteria including a member of the genera Bacillus and Staphylococcus were significantly associated with metastatic CRCs. (p < 0.05 for all, Fisher’s Exact tests). Conclusions: This study suggests that demonstrating the presence or absence of certain microbes in tumor biopsies could have important therapeutic implications for CRC patients. Only bacteria (no fungi, viruses, archaea, etc.) were found to significantly associate with OS across the entire cohort and within treatment subsets. The presence of bacteria was mostly, but not always, associated with worse OS. Antibiotics targeted towards bacterial species associated with negative outcomes could have the potential to improve OS in CRC patients.