Cirrhosis-associated immune dysfunction (CAID) is an immunological perturbation that develops on top of liver cirrhosis (LC). Immune perturbation directs LC progression to hepatocellular carcinoma (HCC). Innate immune cells, in particular, monocytes, play key roles in inflammation and tumorigenesis. MicroRNAs (miRs) have been regarded as master regulators of the immune networks. We aim to investigate the altered monocytes subsets distribution in LC and subsequent HCC in association with the expression level of plasma homo sapiens (hsa)-miR-21-5p and hsa-miR-155-5p. A step toward non-protein coding (nc) RNA precision medicine based on the immune perturbation, manifested as altered monocytes distribution, on top of LC and HCC. Subjects and Methods: Seventy-nine patients diagnosed with chronic hepatitis C virus (CHCV) infection with LC were enrolled in the current study. Patients were sub-classified into LC group without HCC (n=40), LC with HCC (n=39), and 15 apparently healthy controls. Monocyte subsets frequencies were assessed by flow-cytometry. Real-time quantitative PCR was used to measure plasma hsa-miR-21-5p and hsa-miR-155-5p expression. Results: hsa-miR-21-5p correlated with intermediate monocytes (r=0.30, p=0.007), while hsa-miR-155-5p negatively correlated with nonclassical monocytes (r= -0.316, p=0.005). ROC curve analysis revealed that combining intermediate monocytes frequency and hsa-miR-21 yielded sensitivity= 79.5%, specificity= 75%, and AUC= 0.84. In comparison, AFP yielded a lower sensitivity = 69% and 100% specificity with AUC= 0.85. Logistic regression analysis proved that up-regulation of intermediate monocytes frequency and hsa-miR-21-5p were independent risk factors for LC progression to HCC, after adjustment for co-founders. Conclusion: Monocyte subsets differentiation in HCC was linked to hsa-miR-21-5p and hsa-miR-155-5p. Combined up-regulation of intermediate monocytes frequency and hsa-miR-21-5p expression could be considered a sensitive indicator of LC development to HCC. Circulating intermediate monocytes and hsa-miR-21-5p were independent risk factors for HCC evolution, clinically and in silicoproofed.