Background: Lactate dehydrogenase (LDH) has been proved to be a prognostic factor for the severity and poor outcomes of coronavirus disease 2019 (COVID-19). In most studies, patients with various levels of COVID-19 severity were pooled and analyzed which may prevent accurate evaluation of the relationship between LDH and disease progression and in-hospital death. In this study, we aimed to evaluate the association of LDH with in-hospital mortality in severe and critically ill patients with COVID-19. Methods: This single-center retrospective study enrolled 119 patients. Survival curves were plotted using Kaplan-Meier method and compared by log-rank test. Multivariate Cox regression models were used to determine the independent risk factors for in-hospital mortality. Receiver-operator curves (ROCs) were constructed to evaluate the predictive accuracy of LDH and other prognostic biomarkers. Results: Compared to the survival group, LDH levels in the dead group were significantly higher [559.5 (172, 7575) U/L vs 228 (117, 490) U/L, (P < 0.001)]. In Multivariate Cox regression, it remained an independent risk factor for in-hospital mortality (Hazard ratio 5.985, 95.0%CI: 1.498-23.905; P=0.011). A cutoff value of 353.5 U/L predicted the in-hospital mortality with a sensitivity of 94.4% and a specificity of 89.2% respectively. Conclusion: LDH is a favorable prognostic biomarker with high accuracy for predicting in-hospital mortality in severe and critically ill patients with COVID-19. This may direct physicians worldwide to effectively prioritize resources for patients at high risk of death and to implement more aggressive treatments at an earlier phase to save patients’ lives. © The author(s).