BACKGROUND: This study aimed to investigate the potential of circulating small RNAs (sRNAs) as predictive biomarkers for future colorectal cancer (CRC). The study analyzed serum samples from pre-diagnostic CRC patients in two prospective biobanks. METHODS: Serum samples from 142 pre-diagnostic CRC patients, from the Finnish Maternity Cohort (FMC) and The HUNT Study (HUNT2), were subjected to small RNA sequencing. The study compared sRNA expression in CRC cases with controls, considering diverse sRNA classes. RESULTS: Analysis revealed diverse miRNA expression patterns with notable variations in future metastatic cases. Specifically, miR-223-3p and miR-21-5p showed significant up-regulation in future metastatic cases in the FMC cohort. Consistent changes were observed across cohorts, with miR-584-5p, miR-30c-5p, miR-146a-5p, miR-10a-5p, and miR-1306-5p showing up-regulation in future metastatic cases. CONCLUSIONS: The study identified potential serum miRNA biomarkers associated with metastatic CRC, though statistical significance varied. These findings contribute to the understanding of miRNA profiles in pre-diagnostic CRC patients, emphasizing the need for further exploration of non-invasive biomarkers in large prospective studies.