Background: Since colorectal cancer (CRC) remains as the third most common and second most deadly malignant neoplasm, accurate and non-invasive detection technologies became a promising strategy to enhance early diagnosis. Our goal is to develop a liquid biopsy test able to detect methylation-based biomarkers in circulating tumor DNA (ct-DNA) collected from CRC patients' plasma. We are currently working on a digital PCR (dPCR)-based technology focused on detecting with high sensitivity and specificity our proprietary CRC specific epigenetic biomarker panel. Methods: We developed a bioinformatic platform that identifies methylation-based biomarkers from genome-wide Illumina 450K methylation data available in GDC-TCGA public databases. The platform uses multidimensional analysis algorithms and, through a predictive model, establishes a ranking with the most appropriate diagnostic epigenetic biomarkers. First, we tested the selected biomarkers in tumor tissue and in distant colonic mucosa from average risk CRC patients using qPCR. Then, ct-DNA from plasma samples of CRC patients and circulating DNA (cf-DNA) from risk matched negative colonoscopy-confirmed healthy individuals was analyzed by a novel dPCR-based technology in order to detect our panel of epigenetic biomarkers. Lastly, we applied a ROC analysis to the Area Under the Curve (AUC) values and obtained the corresponding sensitivity and specificity results. Results: Illumina 450K methylation data from primary tumor and normal tissue was incorporated into our bioinformatic platform that subsequently ranked 275 candidate genes. Based on several classification criteria we selected a panel composed of the three best ranked candidates. We validated the bioinformatic platform performance in identifying sensitive and specific CRC epigenetic biomarkers by detecting the presence of these biomarkers in tumor mucosa from paired CRC patients and its absence in distant colonic mucosa (n = 20) using qPCR. Furthermore, we applied our dPCR-based technology to simultaneously detect the three-gene panel of epigenetic biomarkers in ctDNA from 34 CRC patients and cfDNA from 33 healthy individuals. We obtained an overall AUC = 0.92, with 76% sensitivity (95% CI: 60-87%) and 90.9% specificity (95% CI: 76-97%). Conclusions: We validated a technology capable of detecting a novel and proprietary methylation-based biomarkers panel. This accurate liquid biopsy technology based on epigenetic biomarker detection applies dPCR and might be implemented in screening or early colorectal cancer detection. Although our technology needs further clinical validations and optimizations, we consider that the obtained results are strong enough to evolve in a complete epigenetic biomarker's blood-based test.