Background: Patients with stage II CRC have a varying survival outcome. Therefore, it is critical to identify new prognostic biomarkers that can help to identify more aggressive forms of the disease. The aim of this study was to identify the potential prognostic value of miRNAs in patients with stage II CRC. Methods: The study included 124 patients with stage II CRC who attended the NCI - Medical Oncology clinics, received treatment and followed-up during the period from January 2004 to December 2014. The expression levels of the five studied miRNAs were examined by qRT-PCR analysis. Additionally, blood samples were drawn from 41 patients recruited in the study in the last 3 years of recruitment to assess the level of miRNAs in blood. Results: In tumor tissues of 124 patients, miR-137, miR-145 and miR-320 were significantly under-expressed in 39.5%, 38.4% and 52.4% of cases, respectively while miR-21 and miR-498 were significantly over-expressed in 48.4% and 40.3%, respectively. On the other hand, assessment of these miRNAs in the blood of 41 cases revealed that miR-137, miR-145 and miR-320 were significantly under-expressed in 46.3%, 46.3% and 51.2% of cases, respectively while miR-21 and miR-498 were significantly over-expressed in 46.3% and 43.9%, respectively. The concordance between tissue and blood was weak with miR-320 and miR-145 (kappa 40-65%), intermediate with miR-498 and miR-137 (kappa 65-75%) while strong concordance has been achieved with miR-21 (kappa 75-85%). Performance status, over-expression of miR-21 and miR-498 and under-expression of miR-137, miR-145, and miR-320 were associated with significantly inferior DFS and OS in univariate analysis. In a multivariate analysis, deregulated miR-498 and miR-320 were independent prognostic factors for worse DFS, while over-expressed miR-498 and miR-21 were found to be independent prognostic factors for inferior OS. Conclusions: MiRNAs play an important role as prognostic markers in stage II CRC patients. Large-scale collaborative efforts are still absolutely essential to aid in determining the clinical potential of miRNAs as diagnostic, prognostic, and predictive biomarkers in CRC in order to achieve better survival outcomes.