Objective To evaluate the role of plasma microRNA-146a (miRNA-146a) in risk prediction and prognosis of the sepsis. Methods A total of 132 sepsis patients admitted to Department of Emergency and Intensive Care Unit (ICU) of Gongli Hospital affiliated to Naval Medical University (Second Military Medical University) between October 2015 and March 2017 and 131 healthy controls were consecutively enrolled in this study. Blood samples from septic patients and healthy controls were collected. Plasma miRNA-146a expression was detected by qRT-PCR. Serum inflammatory cytokines (C-reactive protein[CRP], tumor necrosis factor α[TNF-α], interleukin[IL]-1β, IL-6, IL-8 and IL-10) were detected by enzyme-linked immunosorbent assay (ELISA). Results Low expression of plasma miRNA-146a was found in sepsis patients compared to healthy controls (Z=-7.423, P<0.01). Receiver operating characteristic (ROC) curve revealed that plasma miRNA-146a disclosed a good diagnostic value for sepsis, with an area under curve (AUC) of 0.765 (95% confidence interval[CI] 0.707-0.823); sensitivity and specificity were 87.9% and 61.8% at the best cut-off point, respectively. Multivariate logistic analysis indicated that low plasma miRNA-146a expression was an independent predictive factor for sepsis (odds ratio[OR]=0.312, 95% CI 0.225-0.434, P<0.01). Spearman correlation showed that miRNA-146a expression was negatively correlated with acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score (r=-0.562, P<0.01), CRP (r=-0.304, P<0.001), TNF-α (r=-0.287, P=0.001), IL-1β (r=-0.173, P=0.047) and IL-6 (r=-0.213, P=0.014), while it was positively correlated with IL-10 (r=0.225, P=0.009). miRNA-146a expression in plasma of non-survivors was lower than that in survivors (Z=-2.818, P=0.005). ROC curve revealed that plasma miRNA-146a had a good prognostic value for sepsis, with AUC being 0.660 (95% CI 0.546-0.773), and the sensitivity and specificity were 88.5% and 47.2% at the best cut-off point, respectively. Conclusion Low expression of plasma miRNA-146a is an independent predictive factor for sepsis, and it is correlated with high severity of the disease, high levels of inflammatory cytokine, and poor prognosis.