Aims Many studies have explored the clinical characteristics of patients with coronavirus disease (COVID-19), especially patients with cardiovascular disease. However, associated mechanisms and markers remain to be further investigated. This study aimed to investigate the effect of alpha-hydroxybutyrate dehydrogenase (alpha-HBDH) levels on disease progression and prognosis of patients with COVID-19. Methods and results One thousand seven hundred and fifty-one patients from the Leishenshan hospital in Wuhan were divided into elevated and normal groups by alpha-HBDH level, and the clinical information between the two groups was compared retrospectively. The main outcome evaluation criteria included in-hospital death and disease severity. Univariate and multivariate regression analyses, survival curves, logistic regression, and receiver operating characteristic curve models were performed to explore the relationship between elevated alpha-HBDH and the two outcomes. Besides, curve fitting analyses were conducted to analyse the relationship between computed tomography score and survival. Among 1751 patients with confirmed COVID-19, 15 patients (0.87%) died. The mean (SD) age of patients was 58 years in normal alpha-HBDH group and 66 years in elevated alpha-HBDH group (P < 0.001). The mortality during hospitalization was 0.26% (4 of 1559) for patients with normal alpha-HBDH levels and 5.73% (11 of 192) for those with elevated alpha-HBDH levels (P < 0.001). Multivariate Cox analysis confirmed an association between elevated alpha-HBDH levels and higher risk of in-hospital mortality [hazard ratio: 4.411, 95% confidence interval (95% CI), 1.127-17.260; P = 0.033]. Multivariate logistic regression for disease severity and alpha-HBDH levels showed significant difference between both groups (odds ratio = 3.759; 95% CI, 1.895-7.455; P < 0.001). Kaplan-Meier curves also illustrated the survival difference between normal and elevated alpha-HBDH patients (P < 0.001). Conclusions Our study found that serum alpha-HBDH is an independent risk factor for in-hospital mortality and disease severity among COVID-19 patients. alpha-HBDH assessment may aid clinicians in identifying high-risk individuals among COVID-19 patients.