Background In the context of the COVID-19 outbreak of worldwide, we aim to analyze the laboratory risk factors of in-hospital death in patients with severe COVID-19. Methods All >= 18-year-old patients with confirmed severe COVID-19 admitted to Tongji Hospital (Wuhan, China) from February 3 to February 20, 2020, were retrospectively enrolled and followed up until March 20, 2020. Epidemiological, clinical, laboratory, and treatment data were collected and explored the risk factors associated with in-hospital death. Results A total of 73 severe patients were enrolled in the study, of whom 20 (27%) patients died in hospital during the average 28 days of follow-up period. The median age of non-survivors was significantly older than survivors (69 [64-76.5] years vs 64 [56-71.3] years, P = .033) and 15 (75%) patients were males. The laboratory abnormalities of non-survivors mainly presented in serious inflammation response and multiple organ failure, with high levels of cytokines and deranged coagulation parameters. Multivariable regression showed that neutrophil count greater than 4.47 x 10(9)/L (OR, 58.35; 95%CI: 2.16-1571.69; P = .016), hypersensitivity C-reactive protein greater than 86.7 mg/L (OR, 14.90; 95%CI: 1.29-171.10; P = .030), creatine kinase greater than 101 U/L (OR, 161.62; 95%CI: 6.45-4045.20; P = .002), and blood urea nitrogen greater than 6.7 mmol/L (OR, 11.18; 95%CI: 1.36-91.62; P = .024) were risk factors for in-hospital death. Conclusion The risk factors of neutrophil count, hypersensitivity C-reactive protein, creatine kinase, and blood urea nitrogen could help clinicians to early identify COVID-19 severe patients with poor outcomes on admission. Virus direct attack and cytokine storm play a major role in the death of COVID-19.