BACKGROUND: Colorectal cancer (CRC) ranks as the third most prevalent cancer worldwide. Recent studies suggest the promising potential of microRNAs (miRNA) in predicting the status of circulating tumor cells (CTC), and their combined analyses could pave the way for significant advancements in assessing the risk of metastatic cancer. Here, we investigate the circulating miRNA signatures associated with CTC status in metastatic CRC (mCRC). METHODS: The CTC status of mCRC patients was assessed using AdnaTest ColonCancer technology, which detects tumor cells using an immunomagnetic approach and characterizes them based on colon-specific surface markers. The miRNA profiles were analyzed using the Agilent miRNA microarray in 8 CTC-positive, 8 CTC-negative, and eight healthy individuals. The functional implications of dysregulated miRNAs and their interactions with target mRNAs, TFs, and lncRNAs were determined through a comprehensive in silico analysis. Candidate miRNAs that were differentially expressed in CTC-positive and CTC-negative groups, which have prior evidence for their role in CRC biology, were validated using qPCR. RESULTS: We identified two groups of dysregulated miRNAs associated with CTC status and multiple candidate biomarkers in suggested miRNA regulatory networks. Three miRNAs (hsa-miR-199a-5p, hsa-miR-326, hsa-miR-500b-5p), which were downregulated in the CTC-positive group compared to the CTC-negative group, were confirmed by qPCR and prioritized as candidate predictors of CTC status in mCRC. CONCLUSION: Our findings suggest biomarker candidates that can be used to predict CTC status in individuals with mCRC. This might also provide new insights into new translational medicine applications in the management of mCRC through miRNA-based CRC-associated CTC detection.