Abstract Background Chronic hemodialysis (HD) patients exhibit severe morpho-functional cardiac alterations, posing them at a high risk of death and adverse cardiovascular (CV) outcomes. Despite an unbalanced expression of various microRNAs (miRNAs) has been related to pathological cardiac remodelling and worse CV outcomes, scarce evidence exist on their role in this setting. Methods We evaluated circulating levels of a selected miRNAs panel (30a-5p, 23a-3p, 451a and let7d-5p) in 74 chronic HD patients together with a thorough clinical and echocardiography assessment. Individuals were then prospectly followed (median 22 mo.). The primary endpoint was a composite of all-cause and CV mortality and non-fatal CV events. Results Circulating levels of all miRNAs were lower in HD patients as compared to healthy controls and independently correlated to the severity of cardiac dysfunction. miRNA 30a-5p, 23a-3p and 451a expression was even lower in 30 subjects (40.5%) reaching the composite endpoint (p<0.001), while no differences were reported for let7d-5p. The predictive value of these miRNAs was supported by univariate followed by multivariate Cox-regression analyses (HR ranging from 0.943 to 0.995; p = 0.05 to 0.02) while Kaplan-Meier analyses confirmed a faster progression to the endpoint in individuals displaying miRNA levels below an optimal ROC-derived cut-off value (p ranging from 0.001 to <0.0001; crude HRs 7.95 to 8.61). Conclusions Lower circulating levels of miRNA 30-5p, 23a-3p and 451a in HD patients may reflect cardiac abnormalities and predict a higher risk of worse clinical outcomes in the short-mid term. Future studies on larger HD populations are needed to generalize these findings.