Background & Aims: Gut microbial imbalances are linked to colorectal cancer (CRC), but archae-a's role remains underexplored. Here, we performed bioinformatic and statistical analysis looking for archaeal taxonomic and functional signatures related to CRC. Methods: We analyzed pub-lished fecal metagenomic data from 390 subjects, comparing the archaeomes of CRC and healthy individuals. We conducted a biostatistical analysis to investigate the relationship between Candi-datus Mancarchaeum acidiphilum (DPANN superphylum) and other archaeal species associated with CRC. Using the Prokka tool, we annotated the data focusing on archaeal genes, subsequently linking them to CRC and mapping them against UniprotKB and GO databases for specific ar-chaeal gene functions. Results: Our analysis identified enrichment of methanogenic archaea in healthy subjects, with an exception for Methanobrevibacter smithii, which correlated with CRC. Notably, CRC showed a strong association with archaeal species, particularly Natrinema sp. J7-2, Ferroglobus placidus, and Candidatus Mancarchaeum acidiphilum. Furthermore, the DPANN ar-chaeon exhibited a significant correlation with other CRC-associated archaea (p < 0.001). Func-tionally, we found a marked association between MvhB-type polyferredoxin and colorectal can-cer. We also highlighted the association of archaeal proteins involved in the biosynthesis of leucine and the galactose metabolism process with the healthy phenotype. Conclusion: The archaeomes of CRC patients show identifiable alterations, including a decline in methanogens and an increase in Halobacteria species. MvhB-type polyferredoxin, linked with CRC and species like Candidatus Mancarchaeum acidiphilum, Natrinema sp. J7-2 and Ferroglobus placidus emerge as potential archaeal biomarkers. Archaeal proteins may also offer gut protection, underscoring archaea’s role in CRC dynamics.