Long noncoding RNA HULC is an independent predictor of COVID-19severity and mortality in relation to microRNA-9 and IL-6. Abstract: LncRNA HULC regulates inflammation in vascular endothelial cells resulting in their dysfunction. Endothelial dysfunction contributes to severe COVID-19. lncRNA HULC targetsmiRNA-9 that play roles in the pathogenesis and progression of COVID-19 through the acute inflammatory response mediated by IL-6. This study aimed to evaluate the role of lncRNAHULC,miRNA-9, and IL-6 in estimating the severity and predicting the prognosis of COVID-19. There were 38 non-severe, 38 severe COVID-19 patients, and 38 healthy controls enrolled inthisstudy. Expression of lncRNA HULC and miRNA-9 was performed using RT-qPCR. ELISA was utilized to measure serum IL-6. Expression of lncRNA HULC and IL-6 level were increased in severe patients compared to non-severe patients and controls (p < 0.001). MiRNA-9 showed the lowest expression levels in the severe patients in comparison with non-severe patients and controls (p < 0.001) lncRNA HULC was negatively correlated with miRNA-9 (p < 0.001, r = −0.582) and positively correlated with IL-6 (p < 0.001, r = 0.567). Furthermore, miRNA-9 showed a negative correlation withIL-6(p< 0.001, r = −0.0466). For severity prediction, lncRNA HULC expression had an adjustedORof52.5 (95% CI: 1.43−192.2, p = 0.031). The lncRNA HULC had an adjusted mortality hazardratioof1.9 (95% CI: 1.02−3.56, p = 0.043) after the adjustment of IL-6. So, in COVID-19 patients, the lncRNA HULC had a positive correlation with IL-6 and a negative correlation with miRNA-9. TheCOVID-19 severity and mortality appear to be predicted independently by the lncRNA HULC.