To deepen the understanding of tissue-resident microbiota in colorectal cancer (CRC), we analyzed whole-genome and transcriptome data from 937 patients. We identified 249 genera and 361 species commonly present in both tumors and adjacent normal tissues (NATs). Distinct microbial signatures were associated with anatomical location, tumor stages, hypermutation status, mutations in CRC driver and DNA damage repair genes, as well as consensus molecular subtypes (CMSs). Notably, the presence of the pks island and elevated abundance of Enterobacteriaceae were linked to poor prognosis specifically in CMS2 tumors. Finally, microbial risk scores derived from taxa present in tumor or NATs predicted patient prognosis independently of established clinico-molecular factors. Prognostic taxa were strongly associated with tumor transcriptomic pathways related to hypoxia, immune response, and metabolic status. These findings revealed the heterogeneity of tissue-resident microbiota and their critical role in CRC progression, highlighting potential avenues for targeted intervention.